KR20200005659A - Anti-SIRPα antibodies - Google Patents
Anti-SIRPα antibodies Download PDFInfo
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- KR20200005659A KR20200005659A KR1020197037055A KR20197037055A KR20200005659A KR 20200005659 A KR20200005659 A KR 20200005659A KR 1020197037055 A KR1020197037055 A KR 1020197037055A KR 20197037055 A KR20197037055 A KR 20197037055A KR 20200005659 A KR20200005659 A KR 20200005659A
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- amino acid
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Abstract
본 발명은 항암 요법에 사용하기 적합한 SIRPα에 대한 항체에 관한 것이다. 본 발명은 추가로 인간 고형 종양 및 혈액 악성 종양의 치료에 있어, 경우에 따라 다른 항암 치료제와 조합된, 항-SIRPα 항체의 용도에 관한 것이다.The present invention relates to antibodies against SIRPα that are suitable for use in anticancer therapy. The invention further relates to the use of anti-SIRPα antibodies in the treatment of human solid tumors and hematologic malignancies, optionally in combination with other anticancer therapies.
Description
본 발명은 SIRPα에 대한 항체, 및 암의 치료에 있어, 경우에 따라 다른 항암 치료제와 조합되는, 이들 항체의 용도에 관한 것이다.The present invention relates to antibodies against SIRPα and the use of these antibodies in the treatment of cancer, optionally in combination with other anticancer therapies.
1990년대 후반부터, 치료용 항체가 암의 치료에 이용되어져 왔다. 이들 치료용 항체는 다양한 경로를 통해 악성 세포에 작용할 수 있다. 악성 세포 상의 표적에 대한 항체의 결합에 의해 유발되는 신호 전달 경로는 세포 증식의 억제 또는 아폽토시스를 초래한다. 치료용 항체의 Fc 영역은 보체 의존성 세포독성(CDC), 항체-의존성 세포매개 세포독성(ADCC) 및 항체-의존성 세포성 식작용(ADCP)을 유발할 수있다. 그러나, 치료용 항체는 종종 단일 요법으로서 충분히 효과적이지 않다. 치료용 항체의 효능을 개선하기 위한 한 옵션은 ADCC 및/또는 ADCP의 개선을 통한 것이다. 이것은, 예를 들어 아미노산 치환에 의해, Fcγ 수용체에 대한 Fc 영역의 친화성을 개선시킴으로써(Richards et al. Mol. Cancer Ther. 2008, 7(8), 2517-2527) 또는 Fc 영역의 글리코실화에 영향을 줌으로써(Hayes et al. J. Inflamm. Res. 2016, 9, 209-219) 이루어져 왔다. Since the late 1990s, therapeutic antibodies have been used for the treatment of cancer. These therapeutic antibodies can act on malignant cells through a variety of pathways. Signal transduction pathways caused by the binding of antibodies to targets on malignant cells result in inhibition of cell proliferation or apoptosis. The Fc region of a therapeutic antibody can induce complement dependent cytotoxicity (CDC), antibody-dependent cell mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, therapeutic antibodies are often not effective enough as monotherapy. One option for improving the efficacy of therapeutic antibodies is through improvement of ADCC and / or ADCP. This may be due to, for example, amino acid substitutions to improve the affinity of the Fc region for the Fcγ receptor (Richards et al. Mol. Cancer Ther. 2008, 7 (8), 2517-2527) or to glycosylation of the Fc region. By influence (Hayes et al. J. Inflamm. Res. 2016, 9, 209-219).
치료용 항체의 ADCC 및/또는 ADCP를 개선하는 또 다른 방식은 치료용 항체를 신호 조절 단백질 α에 대한 길항성 항체(항-SIRPα) 또는 항-CD47 항체(WO2009/131453)와 조합하는 것이다. CD47이 단핵구, 대식세포, 수지상 세포 및 호중구에서 발현된 억제성 면역수용체 SIRPα에 결합할 때, SIRPα는 식세포작용 또는 면역 이펙터 세포의 다른 Fc-수용체-의존성 세포 파괴 메커니즘에 의해 암세포의 파괴를 방지하는 억제 신호를 전달한다.Another way to improve the ADCC and / or ADCP of a therapeutic antibody is to combine the therapeutic antibody with an antagonistic antibody (anti-SIRPα) or an anti-CD47 antibody (WO2009 / 131453) against signal regulatory protein α. When CD47 binds to the inhibitory immunoreceptor SIRPα expressed in monocytes, macrophages, dendritic cells and neutrophils, SIRPα prevents the destruction of cancer cells by phagocytosis or other Fc-receptor-dependent cell destruction mechanisms of immune effector cells. It carries a suppression signal.
종양 세포는 치료용 항체에 의해 유도되는 항-종양 면역 반응을 회피하는 메커니즘으로서 CD47의 상향조절을 이용한다. 항-CD47 또는 항-SIRPα 항체는 CD47-SIRPα 축을 통해 생성된 억제성 신호 전달을 차단하여, ADCC 및/또는 ADCP를 증가시킨다. Tumor cells utilize upregulation of CD47 as a mechanism to avoid anti-tumor immune responses induced by therapeutic antibodies. Anti-CD47 or anti-SIRPα antibodies block inhibitory signal transduction generated through the CD47-SIRPα axis, increasing ADCC and / or ADCP.
CD47-SIRPα 상호 작용과 관련된 대부분의 임상 연구는, 단일 요법으로서 그리고 치료용 항체와 조합한 요법으로서, 항-CD47 항체에 중점을 두고있다(Weiskopf. Eur. J. Cancer 2017, 76, 100-109). CD47이 또한 대부분의 정상 조직의 세포 표면에서 발현된다는 사실에도 불구하고, 항암 치료제로서 항-CD47 항체에 관한 연구가 증가하고 있다.Most clinical studies related to CD47-SIRPα interactions focus on anti-CD47 antibodies as monotherapy and in combination with therapeutic antibodies (Weiskopf. Eur. J. Cancer 2017 , 76, 100-109 ). Despite the fact that CD47 is also expressed on the cell surface of most normal tissues, there is increasing research on anti-CD47 antibodies as anticancer agents.
항-SIRPα 항체를 사용한 항암 단일 요법 또는 병용 요법에 대한 연구는 거의 수행되지 않았다. 항-SIRPα 항체에 대한 연구의 대부분은 CD47-SIRPα 상호 작용에 관한 메커니즘적 연구이며 뮤린 항-SIRPα 항체를 사용하여 수행되었으며; 예를 들어, 뮤린 12C4 및 1.23A는 트라스투주맙 옵소닌화된 SKBR3 세포의 호중구 매개 ADCC를 증가시켰다(Zhao et al. PNAS 2011, 108(45), 18342-18347). WO2015/138600은 뮤린 항-인간 SIRPα 항체 KWAR23 및 이의 키메라 Fab 단편을 개시하며, 이는 세툭시맙의 시험관내 식세포작용을 증가시켰다. N297A 돌연변이를 포함하는 인간 IgG1 Fc 부분을 갖는 인간화 KWAR23이 WO2018/026600에 개시되어 있다. WO2013/056352는 IgG4 29AM4-5 및 다른 IgG4 인간 항-SIRPα 항체를 개시한다. 8 mg/kg으로 4주 동안 주당 3회 투여된 IgG4 29AM4-5는 NOD scid 감마(NSG) 마우스의 오른쪽 대퇴골에 주사된 초대 인간 AML 세포의 백혈병 생착을 감소시켰다.Very little research has been conducted on anticancer monotherapy or combination therapy with anti-SIRPα antibodies. Most of the studies on anti-SIRPα antibodies are mechanism studies on CD47-SIRPα interactions and were performed using murine anti-SIRPα antibodies; For example, murine 12C4 and 1.23A increased neutrophil mediated ADCC in trastuzumab opsonized SKBR3 cells (Zhao et al. PNAS 2011, 108 (45), 18342-18347). WO2015 / 138600 discloses murine anti-human SIRPα antibody KWAR23 and chimeric Fab fragments thereof, which increased the in vitro phagocytosis of cetuximab. Humanized KWAR23 with a human IgG 1 Fc moiety comprising an N297A mutation is disclosed in WO2018 / 026600. WO2013 / 056352 discloses IgG 4 29 AM4-5 and other IgG 4 human anti-SIRPα antibodies. IgG 4 29 AM4-5 administered three times per week for 4 weeks at 8 mg / kg reduced leukemia engraftment of primary human AML cells injected into the right femur of NOD scid gamma (NSG) mice.
SIRPα는 면역 이펙터 세포 상에 존재하는 세포외 Ig-유사 도메인을 갖는 막 관통 당단백질인 신호 조절 단백질(SIRP)의 패밀리의 구성원이다. SIRPα의 NH2-말단 리간드 결합 도메인은 고도로 다형이다(Takenaka et al. Nature Immun. 2007, 8(12), 1313-1323). 그러나, 이러한 다형은 CD47에의 결합에 크게 영향을 미치지 않는다. SIRPαBIT(v1) 및 SIRPα1(v2)이 2종의 가장 일반적이고 가장 다양한 (13개의 잔기가 다른) 다형체이다(Hatherley et al. J. Biol. Chem. 2014, 289(14), 10024-10028). 다른 생화학적으로 특징규명된 인간 SIRP 패밀리 구성원은 SIRPβ1, 및 SIRPγ이다.SIRPα is a member of the family of signal regulatory proteins (SIRP), which are membrane transmembrane glycoproteins with extracellular Ig-like domains present on immune effector cells. The NH2-terminal ligand binding domain of SIRPα is highly polymorphic (Takenaka et al. Nature Immun. 2007, 8 (12), 1313-1323). However, this polymorphism does not significantly affect binding to CD47. SIRPα BIT (v1) and SIRPα 1 (v2) are the two most common and most diverse (13 residues different) polymorphs (Hatherley et al. J. Biol. Chem. 2014, 289 (14), 10024- 10028). Other biochemically characterized human SIRP family members are SIRPβ 1 , and SIRPγ.
SIRPβ1은 CD47에 결합하지 않고(van Beek et al. J. Immunol. 2005, 175 (12), 7781-7787, 7788-7789), 적어도 2종의 SIRPβ1 다형 변이(체), SIRPβ1v1(ENSP00000371018) 및 SIRPβ1v2(ENSP00000279477)가 공지되어 있다. SIRPβ1의 천연 리간드가 알려져 있지 않지만, 항-SIRPβ1 특이적 항체를 이용한 시험관내 연구는 SIRPβ1의 관여가 DAP12, Syk 및 SLP-76의 티로신 인산화 및 MEK-MAPK-미오신 경쇄 키나제 캐스케이드의 후속 활성화를 유도함으로써 대식세포에서 식세포작용을 촉진하는 것을 보여준다(Matozaki et al. J. Biol. Chem. 2004, 279(28), 29450-29460). SIRPβ 1 does not bind CD47 (van Beek et al. J. Immunol. 2005, 175 (12), 7781-7787, 7788-7789), at least two SIRPβ 1 polymorphic variants (sieve), SIRPβ 1v1 (ENSP00000371018 ) And SIRPβ 1v2 (ENSP00000279477) are known. Although no natural ligand of SIRPβ 1 is known, in vitro studies with anti-SIRPβ 1 specific antibodies have shown that SIRPβ 1 involvement of tyrosine phosphorylation of DAP12, Syk and SLP-76 and subsequent activation of MEK-MAPK-myosin light chain kinase cascade. It is shown to promote phagocytosis in macrophages by inducing (Matozaki et al. J. Biol. Chem. 2004, 279 (28), 29450-29460).
SIRPγ는 T-세포 및 활성화된 NK-세포에서 발현되고 SIRPα와 비교하여 10 배 낮은 친화도로 CD47에 결합한다. CD47-SIRPγ 상호 작용은 항원-제시 세포와 T-세포 사이의 접촉, T-세포 활성화의 공동-자극 및 T-세포 증식의 촉진에 관여한다(Piccio et al. Blood 2005, 105, 2421-2427). 또한, CD47-SIRPγ 상호 작용은 T-세포의 경내피 이동에서 역할을 한다(Stefanisakis et al. Blood 2008, 112, 1280-1289).SIRPγ is expressed in T-cells and activated NK-cells and binds to CD47 with a 10-fold lower affinity compared to SIRPα. CD47-SIRPγ interactions are involved in contact between antigen-presenting cells and T-cells, co-stimulation of T-cell activation, and promotion of T-cell proliferation (Piccio et al. Blood 2005, 105, 2421-2427). . CD47-SIRPγ interaction also plays a role in endothelial migration of T-cells (Stefanisakis et al. Blood 2008, 112, 1280-1289).
당업계에 공지된 항-SIRPα 항체는 인간 SIRPα에 특이적이지 않거나 너무 특이적이기 때문에 SIRPα 지향의 단일 또는 병용 요법에 사용하기에 덜 적합하다. 종래 기술의 항체 KWAR23, SE5A5, 29AM4-5 및 12C4는 또한 인간 SIRPγ에 결합하기 때문에 특이적이지 않다. T-세포 상에서 발현되는 SIRPγ에 대한 결합은 T-세포 증식 및 동원에 부정적인 영향을 미칠 수 있다. 다른 항-SIRPα 항체는 너무 제한적인 특이성을 가지는데, 예를 들어 1.23A mAb는 인간 SIRPα 다형 변이 SIRPα1만을 인식하며, 적어도 백인 집단에서 우세한 변이 SIRPαBIT는 인식하지 못한다(X.W. Zhao et al. PNAS 2011, 108(45), 18342-18347). Anti-SIRPα antibodies known in the art are less suitable for use in single or combination therapies directed to SIRPα because they are not specific or too specific for human SIRPα. Prior art antibodies KWAR23, SE5A5, 29 AM4-5 and 12C4 are also not specific because they bind to human SIRPγ. Binding to SIRPγ expressed on T-cells can negatively affect T-cell proliferation and recruitment. Other anti-SIRPα antibodies have too limited specificity, for example, 1.23A mAb recognizes only human SIRPα polymorphic variant SIRPα 1 and does not recognize at least the dominant variant SIRPα BIT in the white population (XW Zhao et al. PNAS) . 2011, 108 (45), 18342-18347.
치료용 항체의 ADCC를 증가시키기 위해 항-SIRPα 항체를 사용하는 것 외에도, 이들 항체는 SIRPα-발현 암 유형을 직접 표적화하는데 사용될 수도 있다. 기능적 Fc 영역을 갖는 뮤린 항-SIRPα 항체는 SIRPα를 발현하는 Renca 세포 및 B16BL6 흑색종 세포가 주사된 마우스에서 종양 형성을 늦추기 때문에, 야생형 인간-Fc를 포함하는 항-SIRPα 항체는 신장 세포암종 및 악성 흑색종과 같은 SIRPα를 발현하는 암을 치료하는데 적합할 수 있다(Yanagita et al. JCI Insight 2017, 2(1), e89140).In addition to using anti-SIRPα antibodies to increase the ADCC of therapeutic antibodies, these antibodies may also be used to directly target SIRPα-expressing cancer types. Since murine anti-SIRPα antibodies with functional Fc regions slow tumorigenesis in mice injected with Renca cells expressing SIRPα and B16BL6 melanoma cells, anti-SIRPα antibodies comprising wild-type human-Fc are renal cell carcinoma and malignant It may be suitable for treating cancers that express SIRPα such as melanoma (Yanagita et al. JCI Insight 2017, 2 (1), e89140).
결론적으로, SIRPγ에 대한 결합이 낮고, SIRPα1 및 SIRPαBIT 다형 변이 모두에 특이적으로 결합하고 항암 요법에 단독으로 또는 치료용 항체와 조합하여 사용하기에 적합한, 항-SIRPα 항체에 대한 니즈가 존재한다.In conclusion, there is a need for anti-SIRPα antibodies, which have low binding to SIRPγ and which are specifically bound to both SIRPα 1 and SIRPα BIT polymorphic mutations and are suitable for use in anticancer therapy alone or in combination with therapeutic antibodies. do.
본 발명은 항암 요법에 사용하기 적합한 SIRPα에 대한 항체에 관한 것이다. 본 발명은 또한 인간 고형 종양 및 혈액 악성 종양의 치료에 있어 상기 항체의 용도에 관한 것이다.The present invention relates to antibodies against SIRPα that are suitable for use in anticancer therapy. The invention also relates to the use of said antibody in the treatment of human solid tumors and hematologic malignancies.
도 1. 인간 호중구를 이펙터 세포로서 사용하여 SKBR3 HER2 양성 유방암 세포에서 측정한, 트라스투주맙(Tmab) 단독, 트라스투주맙과 뮤린 12C4 항-SIRPα 항체(mu12C4)의 조합, 트라스투주맙과 뮤린 12C4 가변 영역이 인간 IgG1 불변 영역에 이식된 항체(12C4huIgG1)의 조합, 및 트라스투주맙과 뮤린 12C4 가변 영역이 아미노산 치환 L234A 및 L235A를 포함하는 인간 IgG1 불변 영역에 이식된 항체(12C4huIgG1LALA)의 조합에 있어 %세포독성으로 측정된 ADCC의 비교.
도 2. SKBR3 세포 상에서, 트라스투주맙과, 아미노산 치환 L234A 및 L235A를 포함하는 인간 IgG1 불변 영역을 갖는 항-SIRPα 항체 1-9의 조합, 항-SIRPα 항체 12C4huIgG1LALA(12C4LALA)의 조합 및 항-CD47 항체 B6H12huIgG1LALA(B6H12LALA)의 조합의, 트라스투주맙(100%로 설정)에 대한 %ADCC의 비교. 채워진 사각형(■)은 SIRPαBIT 변이를 갖는 도너(donor)의 호중구로 측정된 값이고, 빈 원형(○)은 SIRPα1 변이를 갖는 도너의 호중구로 측정된 값이다. 열은 모든 도너의 평균이고; 오차 막대는 표준 편차를 나타낸다.
도 3. SKBR3 세포 상에서, 트라스투주맙 단독, 및 트라스투주맙과, 아미노산 치환 L234A 및 L235A를 포함하는 인간 IgG1 불변 영역을 갖는 각종 농도(용량 반응 곡선)의 항-SIRPα 항체 4, 7, 10, 14의 조합, 및 항-SIRPα 항체 12C4huIgG1LALA(12C4LALA)의 조합에 대한 %ADCC의 비교. 두 도너(△,○)의 호중구는 SIRPαBIT 변이를 갖는다. 열은 두 도너의 평균이다.
도 4. SKBR3 세포 상에서, 트라스투주맙 단독, 및 트라스투주맙과, 아미노산 치환 L234A 및 L235A를 포함하는 인간 IgG1 불변 영역을 갖는 항-SIRPα 항체 4, 7, 10, 13, 14, 15 및 16의 조합, 및 항-SIRPα 항체 12C4huIgG1LALA(12C4LALA)와의 조합에 대한 %ADCC의 비교. SIRPαBIT 변이를 갖는 도너의 호중구, SIRPα1 변이를 갖는 도너의 호중구, 및 변이가 확인되지 않은(□) 도너의 호중구가 사용되었다. 열은 도너의 평균이다. Figure 1. Trastuzumab (Tmab) alone, combination of trastuzumab and murine 12C4 anti-SIRPα antibody (mu12C4), trastuzumab and murine 12C4, measured in SKBR3 HER2-positive breast cancer cells using human neutrophils as effector cells Combination of antibody (12C4huIgG 1 ) with variable region implanted in human IgG 1 constant region, and antibody in which trastuzumab and murine 12C4 variable region is implanted in human IgG 1 constant region comprising amino acid substitutions L234A and L235A (12C4huIgG 1 LALA Comparison of ADCC as measured by% cytotoxicity in combination).
Figure 2. Combination of trastuzumab with anti-SIRPα antibody 1-9 with human IgG 1 constant region comprising amino acid substitutions L234A and L235A, combination of anti-SIRPα antibody 12C4huIgG 1 LALA (12C4LALA) on SKBR3 cells Comparison of% ADCC against trastuzumab (set at 100%) of the combination of anti-CD47 antibody B6H12huIgG 1 LALA (B6H12LALA). Filled squares (■) are measured with neutrophils in donors with SIRPα BIT variation, and empty circles (○) are measured with neutrophils in donors with SIRPα 1 variation. Heat is the average of all donors; Error bars represent standard deviation.
Figure 3.
Figure 4.
SIRPα에 대한 승인된 치료제가 입수 가능하지 않지만, 이 표적은 종양 면역 회피 메커니즘에서 중요한 역할을 하는 것으로 밝혀졌다. 나아가, SIRPα는 다양한 악성 세포에서 발현되어 잠재적 종양 관련 항원이 된다.Although no approved therapeutics for SIRPα are available, this target has been found to play an important role in tumor immune evasion mechanisms. Furthermore, SIRPα is expressed in a variety of malignant cells to become potential tumor associated antigens.
본 발명은 2개의 주요 SIRPα 다형 변이 SIRPαBIT 및 SIRPα1에 특이적인 결합을 나타내고, SIRPγ에 결합하지 않으며 치료용 항체의 ADCC 및/또는 ADCP를 증가시키는 길항성 항-SIRPα 항체에 관한 것이다.The present invention provides two main SIRPα polymorphic variants SIRPα BIT and It relates to an antagonistic anti-SIRPα antibody that shows specific binding to SIRPα 1 and does not bind SIRPγ and increases the ADCC and / or ADCP of the therapeutic antibody.
본 명세서 전반에 걸쳐 사용되는 용어 "항체"는 2개의 중쇄 및 2개의 경쇄를 포함하는 모노클로날 항체(mAb)를 지칭한다. 항체는 임의의 이소타입 예컨대 IgA, IgE, IgG, 또는 IgM 항체일 수 있다. 바람직하게는, 항체는 IgG 항체이고, 더 바람직하게는 IgG1 또는 IgG2 항체이다. 항체는 키메라, 인간화 또는 인간 항체일 수 있다. 바람직하게는, 본 발명의 항체는 인간화 항체이다. 더욱 더 바람직하게는, 항체는 인간화 또는 인간 IgG 항체이고, 가장 바람직하게는 인간화 또는 인간 IgG1 mAb이다. 항체는 κ(카파) 또는 λ(람다) 경쇄를 가질 수 있으며, 바람직하게는 κ(카파) 경쇄를 가질 수 있는, 즉, 인간화 또는 인간 IgG1-κ 항체이다. 항체는 조작된 불변 영역을 포함할 수 있으며, 즉, 하나 이상의 돌연변이가 도입되어 예를 들어 반감기를 증가시키고/거나, 이펙터 기능을 증가 또는 감소시킬 수 있다.The term "antibody" as used throughout this specification refers to a monoclonal antibody (mAb) comprising two heavy chains and two light chains. The antibody may be any isotype such as IgA, IgE, IgG, or IgM antibody. Preferably, the antibody is an IgG antibody, more preferably IgG 1 or IgG 2 antibody. The antibody may be a chimeric, humanized or human antibody. Preferably, the antibody of the present invention is a humanized antibody. Even more preferably, the antibody is a humanized or human IgG antibody, most preferably a humanized or human IgG 1 mAb. The antibody may have a κ (kappa) or λ (lambda) light chain and is preferably a humanized or human IgG 1 -κ antibody, which may have a κ (kappa) light chain. The antibody may comprise an engineered constant region, ie one or more mutations may be introduced to, for example, increase half-life and / or increase or decrease effector function.
본원에서 사용된 용어 "모노클로날 항체" 및 "mAb"는 실질적으로 균일한 항체 집단으로부터 수득된 항체를 지칭하며, 즉, 상기 집단을 포함하는 개별 항체는 소량으로 존재할 수 있는 가능한 자연 발생 돌연변이를 제외하고는 동일하다. 항체는 동물을 원하는 항원을 나타내는 펩티드의 혼합물로 면역화함으로써 생성될 수 있다. B-림프구를 단리하고 골수종 세포와 융합시키거나 단일 B-림프구를 조건화된 배지 및 피더 세포의 존재하에 며칠 동안 배양한다. 생성된 항체를 함유하는 골수종 또는 B-림프구 상청액을 검사하여 적합한 B-림프구 또는 하이브리도마를 선택한다. 모노클로날 항체는 문헌[Koehler et al. Nature 1975, 256, 495-497]에 의해 처음 설명한 하이브리도마 방법론에 의해 적합한 하이브리도마로부터 제조될 수 있다. 대안으로, 적합한 B-세포 또는 림프종의 RNA가 용해될 수 있고, RNA가 단리되고 역전사되고 서열분석될 수 있다. 항체는 박테리아, 진핵 동물 또는 식물 세포에서 재조합 DNA 방법에 의해 제조될 수 있다(예를 들어, 미국 특허 제4,816,567호 참조). "모노클로날 항체"는 또한 선행 기술, 예를 들어 문헌[Clackson et al. Nature 1919, 352, 624-628] 및 [Marks et al. J. Mol. Biol. 1991, 222, 581-597]에 기재된 기법을 사용하여 파아지 항체 라이브러리로부터 단리될 수 있다.As used herein, the terms “monoclonal antibody” and “mAb” refer to antibodies obtained from a substantially uniform population of antibodies, that is, individual antibodies comprising such populations may identify possible naturally occurring mutations that may be present in small amounts. Same as except. Antibodies can be generated by immunizing an animal with a mixture of peptides representing the desired antigen. B-lymphocytes are isolated and fused with myeloma cells or a single B-lymphocyte is incubated for several days in the presence of conditioned medium and feeder cells. Myeloma or B-lymphocyte supernatant containing the resulting antibody is examined to select the appropriate B-lymphocyte or hybridoma. Monoclonal antibodies are described in Koehler et al. Nature 1975, 256, 495-497, which may be prepared from suitable hybridomas by the hybridoma methodology described first. Alternatively, RNA of suitable B-cells or lymphomas can be lysed and RNA can be isolated, reverse transcribed and sequenced. Antibodies can be prepared by recombinant DNA methods in bacterial, eukaryotic, or plant cells (see, eg, US Pat. No. 4,816,567). "Monoclonal antibodies" are also described in the prior art, eg, Clackson et al. Nature 1919, 352, 624-628 and Marks et al. J. Mol. Biol. 1991, 222, 581-597 can be isolated from phage antibody library using the technique described.
본 명세서 전반에 걸쳐 사용된 용어 "항원 결합 단편"은 Fab, Fab' 또는 F(ab')2 단편, 단일쇄(sc) 항체, scFv, 단일 도메인(sd) 항체, 디아바디, 또는 미니바디를 포함한다.The term “antigen binding fragment” as used throughout this specification refers to Fab, Fab 'or F (ab') 2 fragments, single chain (sc) antibodies, scFv, single domain (sd) antibodies, diabodies, or minibodies. Include.
인간화 항체에서, 중쇄(HC) 및 경쇄(LC)의 가변 영역(VR)에서 항원 결합 상보성 결정 영역(CDR)은 비-인간 종, 통상적으로 마우스, 래트 또는 토끼로부터의 항체에서 유래한다. 이들 비-인간 CDR은, 항체의 기능적 특성, 예컨대 결합 친화성 및 특이성이 보유되도록 하는 방식으로 HC 및 LC의 가변 영역의 인간 프레임워크 영역(FR1, FR2, FR3 및 FR4)과 조합된다. 인간 FR에서 선택된 아미노산이 낮은 면역원성을 유지하면서 결합 친화성을 개선하기 위해 상응하는 오리지널 비-인간 종의 아미노산으로 교환될 수 있다. 대안으로, 오리지널 비-인간 종의 FR의 선택된 아미노산이 항체의 결합 친화성을 유지하면서 면역원성을 감소시키기 위해 상응하는 인간 아미노산으로 교환된다. 이에 인간화 가변 영역은 인간 불변 영역과 조합된다.In humanized antibodies, the antigen binding complementarity determining regions (CDRs) in the variable regions (VR) of the heavy (HC) and light chain (LC) are derived from antibodies from non-human species, typically mice, rats or rabbits. These non-human CDRs are combined with the human framework regions (FR1, FR2, FR3 and FR4) of the variable regions of HC and LC in a manner such that the functional properties of the antibody such as binding affinity and specificity are retained. Amino acids selected from human FRs can be exchanged with amino acids of the corresponding original non-human species to improve binding affinity while maintaining low immunogenicity. Alternatively, selected amino acids of the FRs of the original non-human species are exchanged with the corresponding human amino acids to reduce immunogenicity while maintaining the binding affinity of the antibody. Humanized variable regions are thus combined with human constant regions.
CDR은 카밧(Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD., NIH publication no. 91-3242, pp. 662, 680, 689 (1991)), 쵸티아(Chothia et al., Nature 1989, 342, 877-883) 또는 IMGT(Lefranc, Immunologist 1999, 7, 132-136)의 어프로치를 사용하여 결정될 수 있다. 본 발명의 맥락에서는, Eu 넘버링이 항체의 중쇄 및 경쇄 불변 영역의 위치를 나타내기 위해 사용된다. "Eu 넘버링"이라는 표현은 Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD., NIH publication no. 91-3242, pp. 662, 680, 689 (1991)에서와 같이 Eu 인덱스를 나타낸다.CDRs include Kabat, EA et al ., Sequences of Proteins of Immunological Interest , 5th Ed.Public Health Service, National Institutes of Health, Bethesda, MD., NIH publication no.91-3242, pp. 662, 680, 689 (1991)), Chothia et al., Nature 1989, 342, 877-883) or IMGT (Lefranc,
길항성 항체는 특정 항원에 대한 친화성을 가지며, 항체의 이의 항원에 대한 결합은 수용체에서 작용제 또는 역작용제의 기능을 억제한다. 이 경우에, 길항성 항-SIRPα 항체의 SIRPα에 대한 결합은 CD47의 SIRPα에 대한 결합을 방지하거나 또는 CD47-SIRPα 결합에 의해 촉발되는 억제 신호를 방해할 것이다.Antagonistic antibodies have affinity for certain antigens, and binding of the antibodies to their antigens inhibits the function of the agonist or inverse agonist at the receptor. In this case, binding of the antagonistic anti-SIRPα antibody to SIRPα will either prevent binding of CD47 to SIRPα or interfere with the inhibitory signal triggered by CD47-SIRPα binding.
길항성 항-SIRPα 항체는 CD47이 결합하는 동일 부위에 결합하여, CD47에 의한 SIRPα의 라이게이션을 방지하고 결과적으로 면역 이펙터 세포의 Fc-수용체-의존적 작용을 음성으로 조절하는 신호 전달을 억제할 수 있다. 길항성 항-SIRPα 항체는 또한 CD47의 결합 부위와 다른 SIRPα의 부위, 즉, 알로스테릭 부위에 결합하여, 물리적 CD47-SIRPα 상호 작용, 예를 들어 SIRPα의 3차원 형상의 변화에 대한 직접적인 간섭없이 SIRPα의 억제성 신호 전달을 저해한다. 이러한 3차원 형상의 변화는 CD47에 결합할 때 (다운스트림) 신호 전달을 방지한다. SIRPα가 알로스테릭 부위에 결합될 때, CD47은 여전히 SIRPα에 의해 결합될 수 있으며, 이는 CD47이 트롬보스폰딘-1(TSP-1)에 대한 결합에 덜 이용 가능하게 할 수 있다. CD47에 대한 TSP-1의 라이게이션은 예를 들어 T-세포 활성화의 음성 조절에 역할을 담당한다(Soto-Pantoja et al. Crit. Rev. Biochem. Mol. Biol. 2015, 50(3), 212-230).Antagonist anti-SIRPα antibodies bind to the same site to which CD47 binds, which prevents the ligation of SIRPα by CD47 and consequently inhibits signal transduction that negatively regulates the Fc-receptor-dependent action of immune effector cells. have. Antagonistic anti-SIRPα antibodies also bind to a site of SIRPα, ie an allosteric site, that is different from the binding site of CD47, so that there is no direct interference with physical CD47-SIRPα interactions, eg changes in the three-dimensional shape of SIRPα. Inhibits inhibitory signal transduction of SIRPα. This three-dimensional change of shape prevents (downstream) signal transmission when coupled to CD47. When SIRPα is bound to the allosteric site, CD47 can still be bound by SIRPα, which can make CD47 less available for binding to thrombospondin-1 (TSP-1). Ligation of TSP-1 against CD47 plays a role in, for example, negative regulation of T-cell activation (Soto-Pantoja et al. Crit. Rev. Biochem. Mol. Biol. 2015, 50 (3), 212 -230).
본 명세서 전반에 사용되는 용어 "결합 친화성(친화도)"은 특정 항원-항체 상호 작용의 해리 상수(KD)를 지칭한다. KD는 해리 속도(koff) 대 회합 속도(kon)의 비이다. 결과적으로, KD는 koff/kon이고, 몰 농도(M)로서 표현된다. KD가 작을수록 결합 친화성이 강해진다. 전형적으로, KD 값은 표면 플라스몬 공명(SPR)을 이용하여, 전형적으로 당업계에 공지된 방법(예를 들어, E.S. Day et al. Anal. Biochem. 2013, 440, 96-107)을 이용하는 바이오센서 시스템(예를 들어 Biacore®)를 사용하여 결정된다. 용어 "결합 친화성"은 또한 예를 들어 ELISA 어세이로 결정되거나 또는 유세포 분석에 의해 결정된 절반-최대 결합(EC50)을 제공하는 항체의 농도를 지칭할 수 있다.The term "binding affinity (affinity)" as used throughout this specification refers to the dissociation constant (K D ) of a particular antigen-antibody interaction. K D is the ratio of dissociation rate (k off ) to association rate (k on ). As a result, K D is k off / k on and is expressed as molar concentration (M). The smaller K D , the stronger the binding affinity. Typically, K D values are determined using surface plasmon resonance (SPR), typically using methods known in the art (eg, ES Day et al. Anal. Biochem . 2013, 440, 96-107). It is determined using a biosensor system (eg Biacore®). The term “binding affinity” may also refer to the concentration of an antibody that provides half-maximal binding (EC 50 ), as determined, for example, by an ELISA assay or by flow cytometry.
본 명세서 전반에 사용되는 용어 "특이적 결합"은 25℃에서 SPR에 의해 결정시 전형적으로 10-7 M 미만, 예컨대 10-8 M, 10-9 M, 10-10 M, 10-11 M 또는 심지어 그보다 낮은 KD로 항체와 그 항원 간의 결합에 관한 것이다.The term “specific binding” as used throughout this specification is typically less than 10 −7 M, such as 10 −8 M, 10 −9 M, 10 −10 M, 10 −11 M or as determined by SPR at 25 ° C. Even lower K D relates to binding between the antibody and its antigen.
본 명세서 전반에 사용되는 용어 "낮은 친화성"은 문구 "~와 결합하지 않는다" 또는 "~에 결합되지 않는다"와 상호교환 가능하며 ELISA 어세이를 사용하여 결정시 1500 ng/ml 초과의 EC50으로 항체와 그 항원 간의 결합 친화성을 지칭하거나, 또는 SPR에 의해 결정시 고정화된 항원과 항체 간에 특이적 결합이 관찰되지 않음을 지칭한다.The term "low affinity" as used throughout this specification is interchangeable with the phrase "does not bind to" or "does not bind to," and EC 50 > 1500 ng / ml, as determined using an ELISA assay. By binding affinity between an antibody and its antigen, or when no specific binding is observed between the immobilized antigen and the antibody as determined by SPR.
본 명세서 전반에 사용되는 용어 "높은 친화성"은 25℃에서 SPR에 의해 결정시 전형적으로 10-10 M 미만, 10-11 M 또는 심지어 그보다 낮은 KD로 항체와 그 항원 간의 결합 친화성을 지칭한다. As used throughout this specification, the term “high affinity” refers to the binding affinity between an antibody and its antigen, typically less than 10 −10 M, 10 −11 M or even lower K D as determined by SPR at 25 ° C. do.
특히, 본 발명은 하기로 이루어진 군에서 선택된 중쇄(HC) 및 경쇄(LC) 가변 영역(VR) 상보성 결정 영역(CDR)을 포함하는 항-SIRPα 항체 또는 이의 항원 결합 단편에 관한 것이다:In particular, the present invention relates to an anti-SIRPα antibody or antigen binding fragment thereof comprising a heavy chain (HC) and a light chain (LC) variable region (VR) complementarity determining region (CDR) selected from the group consisting of:
a. 서열 번호 1의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 2의 CDR1, CDR2 및 CDR3 아미노산 서열;a. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 1 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 2;
b. 서열 번호 3의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 4의 CDR1, CDR2 및 CDR3 아미노산 서열;b. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 3 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 4;
c. 서열 번호 5의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 6의 CDR1, CDR2 및 CDR3 아미노산 서열;c. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 5 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 6;
d. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열;d. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8;
e. 서열 번호 9의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 10의 CDR1, CDR2 및 CDR3 아미노산 서열;e. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 9 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 10;
f. 서열 번호 11의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 12의 CDR1, CDR2 및 CDR3 아미노산 서열;f. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 11 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 12;
g. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열;g. The CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13 and the CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14;
h. 서열 번호 15의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 16의 CDR1, CDR2 및 CDR3 아미노산 서열; 및h. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 15 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 16; And
i. 서열 번호 17의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 18의 CDR1, CDR2 및 CDR3 아미노산 서열, i. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 17 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 18,
여기서 CDR은 카밧 넘버링에 따라 결정된다.Where CDR is determined by Kabat numbering.
바람직하게는, 본 발명은 하기로 이루어진 군에서 선택된 중쇄(HC) 및 경쇄(LC) 가변 영역(VR) 상보성 결정 영역(CDR)을 포함하는 항-SIRPα 항체 또는 이의 항원 결합 단편에 관한 것이다:Preferably, the present invention relates to an anti-SIRPα antibody or antigen binding fragment thereof comprising a heavy chain (HC) and light chain (LC) variable region (VR) complementarity determining region (CDR) selected from the group consisting of:
a. 서열 번호 3의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 4의 CDR1, CDR2 및 CDR3 아미노산 서열;a. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 3 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 4;
b. 서열 번호 5의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 6의 CDR1, CDR2 및 CDR3 아미노산 서열;b. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 5 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 6;
c. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열;c. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8;
d. 서열 번호 9의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 10의 CDR1, CDR2 및 CDR3 아미노산 서열;d. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 9 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 10;
e. 서열 번호 11의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 12의 CDR1, CDR2 및 CDR3 아미노산 서열;e. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 11 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 12;
f. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열;f. The CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13 and the CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14;
g. 서열 번호 15의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 16의 CDR1, CDR2 및 CDR3 아미노산 서열; 및g. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 15 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 16; And
h. 서열 번호 17의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 18의 CDR1, CDR2 및 CDR3 아미노산 서열,h. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 17 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 18,
여기서 CDR은 카밧 넘버링에 따라 결정된다.Where CDR is determined by Kabat numbering.
더 바람직하게는, 본 발명은 하기로 이루어진 군에서 선택된 HCVR 및 LCVR CDR을 포함하는 항-SIRPα 항체 또는 이의 항원 결합 단편에 관한 것이다:More preferably, the present invention relates to an anti-SIRPα antibody or antigen-binding fragment thereof comprising HCVR and LCVR CDRs selected from the group consisting of:
a. 서열 번호 3의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 4의 CDR1, CDR2 및 CDR3 아미노산 서열;a. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 3 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 4;
b. 서열 번호 5의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 6의 CDR1, CDR2 및 CDR3 아미노산 서열;b. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 5 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 6;
c. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열;c. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8;
d. 서열 번호 9의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 10의 CDR1, CDR2 및 CDR3 아미노산 서열; 및d. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 9 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 10; And
e. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열,e. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14,
여기서 CDR은 카밧 넘버링에 따라 결정된다.Where CDR is determined by Kabat numbering.
더욱 더 바람직하게는, 본 발명은 하기로 이루어진 군에서 선택된 HCVR 및 LCVR CDR을 포함하는 항-SIRPα 항체 또는 이의 항원 결합 단편에 관한 것이다:Even more preferably, the invention relates to an anti-SIRPα antibody or antigen binding fragment thereof comprising HCVR and LCVR CDRs selected from the group consisting of:
a. 서열 번호 5의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 6의 CDR1, CDR2 및 CDR3 아미노산 서열; a. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 5 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 6;
b. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열; 및b. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8; And
c. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열,c. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14,
여기서 CDR은 카밧 넘버링에 따라 결정된다.Where CDR is determined by Kabat numbering.
가장 바람직하게는, 본 발명은 하기로 이루어진 군에서 선택된 HCVR 및 LCVR CDR을 포함하는 항-SIRPα 항체 또는 이의 항원 결합 단편에 관한 것이다:Most preferably, the invention relates to an anti-SIRPα antibody or antigen binding fragment thereof comprising HCVR and LCVR CDRs selected from the group consisting of:
a. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열; 및a. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8; And
b. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열, b. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14,
여기서 CDR은 카밧 넘버링에 따라 결정된다.Where CDR is determined by Kabat numbering.
바람직한 실시양태에서, 본 발명은 앞서 정의된 바와 같은 항-SIRPα 항체 또는 이의 항원 결합 단편에 관한 것으로, 여기서 항체는 SIRPαBIT 및 SIRPα1 둘 모두에 특이적인 결합을 나타내고 SIRPγ에 결합하지 않는다.In a preferred embodiment, the invention relates to an anti-SIRPα antibody or antigen binding fragment thereof as defined above, wherein the antibody is a SIRPα BIT and It exhibits specific binding to both SIRPα 1 and does not bind SIRPγ.
보다 바람직한 실시양태에서, 항-SIRPα 항체 또는 이의 항원 결합 단편은 10-9 M 미만의 KD로 SIRPαBIT에 특이적으로 결합하고 10-7 M 미만의 KD로 SIRPα1에 특이적으로 결합하며, 여기서 KD는 25℃에서 SPR로 측정된다. 바람직하게는, 항-SIRPα 항체 또는 이의 항원 결합 단편은 10-8 M 미만의 KD로 SIRPα1에 결합한다.In a more preferred embodiment, the anti-SIRPα antibody or antigen binding fragment thereof specifically binds SIRPα BIT with a K D of less than 10 −9 M and specifically binds SIRPα 1 with a K D of less than 10 −7 M , Where K D is measured by SPR at 25 ° C. Preferably, the anti-SIRPα antibody or antigen binding fragment thereof binds SIRPα 1 with a K D of less than 10 −8 M.
또 다른 더 바람직한 실시양태에서, 항-SIRPα 항체 또는 이의 항원 결합 단편은 10-9 M 미만의 KD로 SIRPαBIT 및 SIRPα1에 특이적으로 결합하며, 여기서 KD는 25℃에서 SPR로 측정된다.In another more preferred embodiment, the anti-SIRPα antibody or antigen binding fragment thereof has a SIRPα BIT with a K D of less than 10 −9 M and Specifically binds to SIRPα 1 , where K D is measured by SPR at 25 ° C. FIG.
더욱 더 바람직한 실시양태에서, 항-SIRPα 항체 또는 이의 항원 결합 단편은 10-10 M 미만의 KD로 SIRPαBIT 및 SIRPα1에 특이적으로 결합한다. 바람직하게는, 항-SIRPα 또는 이의 항원 결합 단편 항체는 10-10 M 미만의 KD로 SIRPαBIT와 특이적으로 결합하고 10-11 M 미만의 KD로 SIRPα1과 특이적으로 결합한다. 전형적으로, 앞서 정의된 항-SIRPα 항체는 키메라, 인간화 또는 인간 항체이다. 바람직하게는, 항-SIRPα 항체는 인간화 또는 인간 항체이다. 더 바람직하게는, 항-SIRPα 항체는 인간화 항체이다. 특정의 실시양태에서, 본 발명에 따른 인간화 항-SIRPα 항체 또는 이의 항원 결합 단편은 하기로 이루어진 군에서 선택된 HCVR 및 LCVR을 포함한다:In even more preferred embodiments, the anti-SIRPα antibody or antigen-binding fragment thereof has a SIRPα BIT with a K D of less than 10 −10 M and Binds specifically to SIRPα 1 . Preferably, the anti-SIRPα or antigen-binding fragment antibody thereof specifically binds SIRPα BIT with a K D of less than 10 −10 M and specifically with SIRPα 1 with a K D of less than 10 −11 M. Typically, the anti-SIRPα antibodies as defined above are chimeric, humanized or human antibodies. Preferably, the anti-SIRPα antibody is a humanized or human antibody. More preferably, the anti-SIRPα antibody is a humanized antibody. In certain embodiments, humanized anti-SIRPα antibodies or antigen binding fragments thereof according to the present invention comprise HCVRs and LCVRs selected from the group consisting of:
a. 서열 번호 30의 HCVR 아미노산 서열 및 서열 번호 31의 LCVR 아미노산 서열;a. The HCVR amino acid sequence of SEQ ID NO: 30 and the LCVR amino acid sequence of SEQ ID NO: 31;
b. 서열 번호 32의 HCVR 아미노산 서열 및 서열 번호 33의 LCVR 아미노산 서열;b. The HCVR amino acid sequence of SEQ ID NO: 32 and the LCVR amino acid sequence of SEQ ID NO: 33;
c. 서열 번호 34의 HCVR 아미노산 서열 및 서열 번호 8의 LCVR 아미노산 서열;c. The HCVR amino acid sequence of SEQ ID NO: 34 and the LCVR amino acid sequence of SEQ ID NO: 8;
d. 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 36의 LCVR 아미노산 서열;d. The HCVR amino acid sequence of SEQ ID NO: 35 and the LCVR amino acid sequence of SEQ ID NO: 36;
e. 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열;e. The HCVR amino acid sequence of SEQ ID NO: 35 and the LCVR amino acid sequence of SEQ ID NO: 37;
f. 서열 번호 13의 HCVR 아미노산 서열 및 서열 번호 38의 LCVR 아미노산 서열; 및f. The HCVR amino acid sequence of SEQ ID NO: 13 and the LCVR amino acid sequence of SEQ ID NO: 38; And
g. 서열 번호 13의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열.g. The HCVR amino acid sequence of SEQ ID NO: 13 and LCVR amino acid sequence of SEQ ID NO: 37.
바람직한 실시양태에서, 인간화 항-SIRPα 항체 또는 이의 항원 결합 단편은 서열 번호 30의 HCVR 아미노산 서열 및 서열 번호 31의 LCVR 아미노산 서열을 포함한다.In a preferred embodiment, the humanized anti-SIRPα antibody or antigen binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 30 and the LCVR amino acid sequence of SEQ ID NO: 31.
또 다른 바람직한 실시양태에서, 인간화 항-SIRPα 항체 또는 이의 항원 결합 단편은 서열 번호 32의 HCVR 아미노산 서열 및 서열 번호 33의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, the humanized anti-SIRPα antibody or antigen binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 32 and the LCVR amino acid sequence of SEQ ID NO: 33.
또 다른 바람직한 실시양태에서, 인간화 항-SIRPα 항체 또는 이의 항원 결합 단편은 서열 번호 34의 HCVR 아미노산 서열 및 서열 번호 8의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, the humanized anti-SIRPα antibody or antigen binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 34 and the LCVR amino acid sequence of SEQ ID NO: 8.
또 다른 바람직한 실시양태에서, 인간화 항-SIRPα 항체 또는 이의 항원 결합 단편은 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 36의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, the humanized anti-SIRPα antibody or antigen binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 35 and the LCVR amino acid sequence of SEQ ID NO: 36.
또 다른 바람직한 실시양태에서, 인간화 항-SIRPα 항체 또는 이의 항원 결합 단편은 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, the humanized anti-SIRPα antibody or antigen binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 35 and the LCVR amino acid sequence of SEQ ID NO: 37.
또 다른 바람직한 실시양태에서, 인간화 항-SIRPα 항체 또는 이의 항원 결합 단편은 서열 번호 13의 HCVR 아미노산 서열 및 서열 번호 38의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, the humanized anti-SIRPα antibody or antigen binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 13 and the LCVR amino acid sequence of SEQ ID NO: 38.
또 다른 바람직한 실시양태에서, 인간화 항-SIRPα 항체 또는 이의 항원 결합 단편은 서열 번호 13의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, the humanized anti-SIRPα antibody or antigen binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 13 and the LCVR amino acid sequence of SEQ ID NO: 37.
인간 (hu)SIRPαBIT 및 (hu)SIRPα1 둘 다에 대한 결합 이외에, 본 발명에 따른 항체는 또한 시노몰구스 원숭이 (cy)SIRPα에 결합할 수 있어, 관련 동물 모델에서 생체내 연구를 가능하게 한다.Human (hu) SIRPα BIT and In addition to binding to both (hu) SIRPα 1 , the antibodies according to the invention can also bind to cynomolgus monkey (cy) SIRPα, allowing for in vivo studies in relevant animal models.
본 발명에 따른 항체는 CD47의 결합 부위와 다른 SIRPα의 부위, 즉, 알로스테릭 부위에 결합하여 물리적 CD47-SIRPα 상호작용에 대한 직접적인 간섭없이 SIRPα의 억제성 신호 전달을 저해할 수 있다. 대안으로, 항체는 CD47이 결합하는 동일한 부위에 결합할 수 있어, CD47에 의한 SIRPα의 라이게이션을 방지하고 그 결과 면역 이펙터 세포의 Fc-수용체-의존적 작용을 음성으로 조절하는 신호 전달을 억제할 수 있다.The antibody according to the present invention can bind to the site of SIRPα different from the binding site of CD47, ie, the allosteric site, and inhibit the inhibitory signal transduction of SIRPα without direct interference with physical CD47-SIRPα interaction. Alternatively, the antibody may bind to the same site to which CD47 binds, thus preventing the ligation of SIRPα by CD47 and thus inhibiting signal transduction that negatively modulates the Fc-receptor-dependent action of immune effector cells. have.
앞서 기재된 항-SIRPα 항체 또는 이의 항원 결합 단편은 공지의 항-SIRPα 항체보다 특이적이며, SIRPαBIT 및 SIRPα1 둘 다에 대해 우수한 친화성을 나타낸다. 또한, 본 발명에 따른 항-SIRPα 항체는 SIRPγ에 결합하지 않는다. The anti-SIRPα antibodies or antigen binding fragments thereof described above are more specific than known anti-SIRPα antibodies, and include SIRPα BIT and Good affinity for both SIRPα 1 . In addition, the anti-SIRPα antibodies according to the present invention do not bind SIRPγ .
일 특정 실시양태에서, 본 발명에 따른 항-SIRPα 항체는 인간 면역 이펙터 세포에 존재하는 활성화 Fc 수용체에 결합하는 Fc 영역을 포함한다. 이러한 항-SIRPα 항체는 ADCC 및/또는 ADCP를 유발할 수 있기 때문에 SIRPα-양성 인간 고형 종양 및 혈액 악성 종양의 단일 요법에 적합하다. 인간 면역 이펙터 세포는 각종 활성화 Fc 수용체를 보유하며, 라이게이션시 식세포작용, 사이토카인 방출, ADCC 및/또는 ADCP, 등을 촉발한다. 이러한 수용체의 예는 Fcγ 수용체, 예를 들어 FcγRI(CD64), FcγRIIA(CD32), FcγRIIIA(CD16a), FcγRIIIB(CD16b), FcγRIIC 및 Fcα 수용체 FcαRI(CD89)이다. 다양한 천연 항체 이소타입이 이들 수용체에 결합한다. 예를 들어 IgG1은 FcγRI, FcγRIIA, FcγRIIC, FcγRIIIA, FcγRIIIB에 결합하고; IgG2는 FcγRIIA, FcγRIIC, FcγRIIIA에 결합하고; IgG3은 FcγRI, FcγRIIA, FcγRIIC, FcγRIIIA, FcγRIIIB에 결합하고; IgG4는 FcγRI, FcγRIIA, FcγRIIC, FcγRIIIA에 결합하고; IgA는 FcαRI에 결합한다. In one specific embodiment, an anti-SIRPα antibody according to the present invention comprises an Fc region that binds to an activating Fc receptor present in human immune effector cells. Such anti-SIRPα antibodies are suitable for monotherapy of SIRPα-positive human solid tumors and hematologic malignancies because they can induce ADCC and / or ADCP. Human immune effector cells possess various activating Fc receptors and trigger phagocytosis, cytokine release, ADCC and / or ADCP, etc., upon ligation. Examples of such receptors are Fcγ receptors such as FcγRI (CD64), FcγRIIA (CD32), FcγRIIIA (CD16a), FcγRIIIB (CD16b), FcγRIIC and Fcα receptors FcαRI (CD89). Various natural antibody isotypes bind to these receptors. For example IgG 1 binds to FcγRI, FcγRIIA, FcγRIIC, FcγRIIIA, FcγRIIIB; IgG 2 binds to FcγRIIA, FcγRIIC, FcγRIIIA; IgG 3 binds to FcγRI, FcγRIIA, FcγRIIC, FcγRIIIA, FcγRIIIB; IgG 4 binds to FcγRI, FcγRIIA, FcγRIIC, FcγRIIIA; IgA binds to FcαRI.
바람직한 실시양태에서, 본 발명에 따른 항-SIRPα 항체는 IgA 또는 IgG 이소타입의 Fc 영역을 포함한다. IgG1, IgG2, IgG3 또는 IgG4 이소타입의 Fc 영역을 포함하는 항-SIRPα 항체가 보다 바람직하고; IgG1, IgG2 또는 IgG4 이소타입이 더욱 더 바람직하다. IgG1 이소타입의 Fc 영역을 포함하는 항-SIRPα 항체가 가장 바람직하다.In a preferred embodiment, the anti-SIRPα antibody according to the invention comprises the Fc region of the IgA or IgG isotype. IgG 1 , IgG 2 , IgG 3 or More preferred are anti-SIRPα antibodies comprising an Fc region of an IgG 4 isotype; IgG 1 , IgG 2 or Even more preferred is the IgG 4 isotype. Most preferred are anti-SIRPα antibodies comprising the Fc region of an IgG 1 isotype.
인간 면역 이펙터 세포에 존재하는 활성화 Fc 수용체에 결합하는 Fc 영역을 포함하는 항-SIRPα 항체가 SIRPα를 발현하는 암을 치료하는데 적합할 수 있지만, 키메라 항-SIRPα IgG1 항체는, 인간 면역 이펙터 세포에 존재하는 활성화 Fc 수용체에 결합하는 인간 Fc 영역을 포함하는 다른 항체(즉, ADCC 및/또는 ADCP를 유발할 수 있는 항체)와 함께 시험관내에서 시험했을 때 예상된 결과를 나타내지 않았다. 시험관내 ADCC 어세이의 결과는, 키메라 IgG1 항-SIRPα 항체가 뮤린 항체를 사용한 이전의 결과에 기초하여 예상되는 만큼, 그러한 다른 항체의 ADCC를 증가시키지 않는다는 것을 보여주었다. While anti-SIRPα antibodies comprising Fc regions that bind to activating Fc receptors present in human immune effector cells may be suitable for treating cancer expressing SIRPα, chimeric anti-SIRPα IgG 1 antibodies may be directed to human immune effector cells. When tested in vitro with other antibodies comprising a human Fc region that binds to an activating Fc receptor present (ie, antibodies capable of inducing ADCC and / or ADCP), the expected results were not shown. The results of the in vitro ADCC assay showed that the chimeric IgG 1 anti-SIRPα antibody did not increase the ADCC of such other antibodies as expected based on previous results with murine antibodies.
따라서, 본 발명은 인간 면역 이펙터 세포에 존재하는 활성화 Fc 수용체에 대해 감소된 결합 또는 낮은 친화성을 나타내는 항-SIRPα 항체에 관한 것이다. 이러한 항-SIRPα 항체는 유사한 비변경된 Fc 영역과 비교했을 때 하나 이상의 아미노산이 (또)다른 아미노산(들)으로 치환된 변경된 Fc 영역을 포함한다. 감소된 결합은, 활성화 Fc 수용체에 대해 변경된 Fc 영역을 포함하는 항-SIRPα 항체의 친화성이 유사한 비변경된 Fc 영역을 포함하는 동일한 가변 영역을 갖는 항-SIRPα 항체의 친화성보다 낮다는 것을 의미한다. 활성화 Fc 수용체에 대한 항체의 결합 친화성은 전형적으로 당업계에 공지된 방법, 예를 들어 문헌[Harrison et al. in J. Pharm. Biomed. Anal. 2012, 63, 23-28]의 방법을 사용하여 표면 플라스몬 공명(SPR) 또는 유세포 분석에 의해 측정된다. 인간 Fcα 또는 Fcγ 수용체에 대해 감소된 결합 또는 낮은 친화성을 나타내는 항체는, 치료용 항체와 조합되어, 이펙터 면역 이펙터 세포의 ADCC 및/또는 ADCP를 증가시킴으로써 암세포의 세포 파괴에 특히 효과적이다. 전형적으로, 본 발명에 따른 항-SIRPα 항체의 Fc 영역은 인간 면역 이펙터 세포에 존재하는 활성화 Fc 수용체에 대한 결합을 감소시키도록 변경된다. Thus, the present invention relates to anti-SIRPα antibodies that exhibit reduced binding or low affinity for activating Fc receptors present in human immune effector cells. Such anti-SIRPα antibodies comprise altered Fc regions in which one or more amino acids are replaced by (and) other amino acid (s) as compared to similar unaltered Fc regions. Reduced binding means that the affinity of an anti-SIRPα antibody comprising an altered Fc region for an activating Fc receptor is lower than the affinity of an anti-SIRPα antibody having the same variable region comprising a similar unaltered Fc region. . The binding affinity of an antibody for an activating Fc receptor is typically determined by methods known in the art, such as Harrison et al . in J. Pharm. Biomed. Anal. 2012, 63, 23-28] is measured by surface plasmon resonance (SPR) or flow cytometry. Antibodies that exhibit reduced binding or low affinity for human Fcα or Fcγ receptors, in combination with therapeutic antibodies, are particularly effective at destroying cells of cancer cells by increasing ADCC and / or ADCP of effector immune effector cells. Typically, the Fc region of an anti-SIRPα antibody according to the invention is altered to reduce binding to activating Fc receptors present in human immune effector cells.
따라서, 본 발명에 따른 항-SIRPα 항체는, 인간 Fcα 또는 Fcγ 수용체에 대해 감소된 결합 또는 낮은 친화성을 나타내는 변경된 Fc 영역을 포함한다. 예를 들면, Fcγ 수용체에 대한 IgG1 결합은 L234, L235, G237, D265, D270, N297, A327, P328, 및 P329 (Eu 넘버링)으로 이루어진 군에서 선택되는 하나 이상의 IgG1 아미노산을 치환함으로써 감소될 수 있고; IgG2 결합은 예를 들어 이하의 아미노산 치환 V234A, G237A, P238S, H268A, V309L, A330S, 및 P331S; 또는 H268Q, V309L, A330S, 및 P331S (IgG1 Eu 넘버링에 유사한 넘버링) (Vafa et al. Methods 2014, 65, 114-126) 중 하나 이상을 도입함으로써 감소될 수 있고; IgG3 결합은 예를 들어 아미노산 치환 L234A 및 L235A, 또는 아미노산 치환 L234A, L235A 및 P331S (Leoh et al. Mol. Immunol. 2015, 67, 407-415)을 도입함으로써 감소될 수 있고; IgG4 결합은 예를 들어 아미노산 치환 S228P, F234A 및 L235A (IgG1 Eu 넘버링에 유사한 넘버링) (Parekh et al. mAbs 2012, 4(3), 310-318)를 도입함으로써 감소될 수 있다. Fcα 수용체에 대한 IgA 결합은 예를 들어 아미노산 치환 L257R, P440A, A442R, F443R, 및 P440R (순차적 넘버링, Pleass et al. J. Biol. Chem. 1999, 271(33), 23508-23514) 중 하나 이상을 도입함으로써 감소될 수 있다.Thus, anti-SIRPα antibodies according to the present invention comprise altered Fc regions that exhibit reduced binding or low affinity for human Fcα or Fcγ receptors. For example, IgG 1 binding to the Fcγ receptor can be reduced by substituting one or more IgG 1 amino acids selected from the group consisting of L234, L235, G237, D265, D270, N297, A327, P328, and P329 (Eu numbering). Can; IgG 2 binding is for example the following amino acid substitutions V234A, G237A, P238S, H268A, V309L, A330S, and P331S; Or by introducing one or more of H268Q, V309L, A330S, and P331S (numbering similar to IgG 1 Eu numbering) (Vafa et al. Methods 2014, 65, 114-126); IgG 3 binding can be reduced, for example, by introducing amino acid substitutions L234A and L235A, or amino acid substitutions L234A, L235A and P331S (Leoh et al. Mol. Immunol . 2015, 67, 407-415); IgG 4 binding can be reduced, for example, by introducing amino acid substitutions S228P, F234A and L235A (numbering similar to IgG 1 Eu numbering) (Parekh et al. MAbs 2012, 4 (3), 310-318). IgA binding to the Fcα receptor is for example at least one of amino acid substitutions L257R, P440A, A442R, F443R, and P440R (sequential numbering, Pleass et al . J. Biol. Chem. 1999, 271 (33), 23508-23514) Can be reduced by introducing.
바람직하게는, 본 발명에 따른 항-SIRPα 항체는, 인간 Fcγ 수용체에 대해 감소된 결합 또는 낮은 친화성을 나타내는 변경된 Fc 영역을 포함한다. 더 바람직하게는, 변경된 Fc 영역은 IgG 이소타입의 Fc 영역이다. 더욱 더 바람직하게는, 변경된 Fc 영역은 IgG1, IgG2 또는 IgG4 이소타입의 Fc 영역이다.Preferably, the anti-SIRPα antibody according to the present invention comprises an altered Fc region which exhibits reduced binding or low affinity for human Fcγ receptors. More preferably, the altered Fc region is an Fc region of the IgG isotype. Even more preferably, the altered Fc region is IgG 1 , IgG 2 or Fc region of IgG 4 isotype.
바람직한 실시양태에서, 본 발명에 따른 항-SIRPα 항체는 L234, L235, G237, D265, D270, N297, A327, P328, 및 P329 (Eu 넘버링)으로 이루어진 군에서 선택된 하나 이상의 위치에 하나 이상의 아미노산 치환을 포함하는 변경된 인간 IgG1 Fc 영역을 포함한다.In a preferred embodiment, the anti-SIRPα antibody according to the invention comprises one or more amino acid substitutions in one or more positions selected from the group consisting of L234, L235, G237, D265, D270, N297, A327, P328, and P329 (Eu numbering) Including an altered human IgG 1 Fc region.
바람직하게는, 항-SIRPα 항체는, 아미노산 치환 N297A 또는 N297G의 어느 것도 포함하지 않는 변경된 Fc IgG1 영역을 포함한다. 더 바람직하게는, 항-SIRPα 항체는, 위치 N297에서 아미노산 치환을 포함하지 않는 변경된 Fc IgG1 영역을 포함한다.Preferably, the anti-SIRPα antibody comprises an altered Fc IgG 1 region that does not contain any of amino acid substitutions N297A or N297G. More preferably, the anti-SIRPα antibody comprises an altered Fc IgG 1 region that does not comprise an amino acid substitution at position N297.
일 실시양태에서, 변경된 인간 IgG1 Fc 영역은 L234A, L234E, L235A, G237A, D265A, D265E, D265N, D270A, D270E, D270N, N297A, N297G, A327Q, P328A, P329A 및 P329G로 이루어진 군에서 선택되는 하나 이상의 아미노산 치환을 포함한다. 바람직하게는, 하나 이상의 아미노산 치환은 L234A, L234E, L235A, G237A, D265A, D265E, D265N, N297A, P328A, P329A 및 P329G로 이루어진 군에서 선택된다.In one embodiment, the modified human IgG 1 Fc region is one selected from the group consisting of L234A, L234E, L235A, G237A, D265A, D265E, D265N, D270A, D270E, D270N, N297A, N297G, A327Q, P328A, P329A and P329G These include amino acid substitutions above. Preferably, at least one amino acid substitution is selected from the group consisting of L234A, L234E, L235A, G237A, D265A, D265E, D265N, N297A, P328A, P329A and P329G.
또 다른 실시양태에서, 변경된 인간 IgG1 Fc 영역은 L234A, L234E, L235A, G237A, D265A, D265E, D265N, D270A, D270E, D270N, A327Q, P328A, P329A 및 P329G로 이루어진 군에서 선택되는 하나 이상의 아미노산 치환을 포함한다. 바람직하게는, 하나 이상의 아미노산 치환은 L234A, L234E, L235A, G237A, D265A, D265E, D265N, P328A, P329A 및 P329G로 이루어진 군에서 선택된다. 더 바람직하게는, 변경된 Fc IgG1 영역은 아미노산 치환 N297A 또는 N297G를 포함하지 않는다. 더욱 더 바람직하게는, 변경된 Fc IgG1 영역은 위치 N297에서 아미노산 치환을 포함하지 않는다.In another embodiment, the modified human IgG 1 Fc region is one or more amino acid substitutions selected from the group consisting of L234A, L234E, L235A, G237A, D265A, D265E, D265N, D270A, D270E, D270N, A327Q, P328A, P329A and P329G It includes. Preferably, at least one amino acid substitution is selected from the group consisting of L234A, L234E, L235A, G237A, D265A, D265E, D265N, P328A, P329A and P329G. More preferably, the altered Fc IgG 1 region does not comprise amino acid substitutions N297A or N297G. Even more preferably, the altered Fc IgG 1 region does not comprise an amino acid substitution at position N297.
바람직한 실시양태에서, 변경된 인간 IgG1 Fc 영역은 아미노산 치환 L234A 및 L235A, L234E 및 L235A, L234A, L235A 및 P329A 또는 L234A, L235A 및 P329G를 포함한다. 바람직하게는, 변경된 Fc IgG1 영역은 아미노산 치환 N297A 또는 N297G를 포함하지 않는다. 더 바람직하게는, 변경된 Fc IgG1 영역은 위치 N297에서 아미노산 치환을 포함하지 않는다.In a preferred embodiment, the modified human IgG 1 Fc region comprises amino acid substitutions L234A and L235A, L234E and L235A, L234A, L235A and P329A or L234A, L235A and P329G. Preferably, the altered Fc IgG 1 region does not comprise amino acid substitution N297A or N297G. More preferably, the altered Fc IgG 1 region does not comprise amino acid substitutions at position N297.
또 다른 바람직한 실시양태에서, 본 발명에 따른 항-SIRPα 항체는, 아미노산 치환 L234A 및 L235A 또는 L234E 및 L235A, 바람직하게는 아미노산 치환 L234A 및 L235A를 포함하는 변경된 인간 IgG1 Fc 영역을 포함한다. 더 바람직하게는, 변경된 Fc IgG1 영역은 아미노산 치환 N297A 또는 N297G를 포함하지 않는다. 더욱 더 바람직하게는, 변경된 Fc IgG1 영역은 위치 N297에서 아미노산 치환을 포함하지 않는다.In another preferred embodiment, the anti-SIRPα antibody according to the invention comprises an altered human IgG 1 Fc region comprising amino acid substitutions L234A and L235A or L234E and L235A, preferably amino acid substitutions L234A and L235A. More preferably, the altered Fc IgG 1 region does not comprise amino acid substitutions N297A or N297G. Even more preferably, the altered Fc IgG 1 region does not comprise an amino acid substitution at position N297.
본 발명은 추가적으로 앞서 기재된 항-SIRPα 항체 및 하나 이상의 약학적으로 허용가능한 부형제를 포함하는 약학 조성물에 관한 것이다. 항체와 같은 치료 용 단백질의 전형적인 약제학적 제제는 정맥내 주입 전에 (수성) 용해(즉, 재구성)를 필요로 하는 동결 건조된 케이크(동결 건조된 분말) 또는 사용 전에 해동이 필요한 동결된 (수성) 용액의 형태를 취한다.The present invention further relates to a pharmaceutical composition comprising the anti-SIRPα antibody described above and one or more pharmaceutically acceptable excipients. Typical pharmaceutical preparations of therapeutic proteins such as antibodies include lyophilized cakes (freeze-dried powders) that require (aqueous) dissolution (ie, reconstitution) prior to intravenous infusion or frozen (aqueous) that require thawing before use. Take the form of a solution.
전형적으로, 약학 조성물은 동결 건조된 케이크의 형태로 제공된다. 본 발명에 따른 (동결 건조 전) 약학 조성물에 포함시키기에 적합한 약학적으로 허용가능한 부형제는 버퍼 용액(예를 들어 물에 시트레이트, 히스티딘 또는 숙시네이트 함유 염), 동결보호제(예를 들어 수크로스, 트레할로스), 등장화제(예를 들어 염화나트륨), 계면활성제(예를 들어 폴리소르베이트), 및 증량제(예를 들어 만니톨, 글리신)를 포함한다. 동결 건조된 단백질 제제에 사용되는 부형제는 동결 건조 공정 동안뿐만 아니라 저장 동안 단백질 변성을 방지하는 능력으로 선택된다.Typically, the pharmaceutical composition is provided in the form of a lyophilized cake. Pharmaceutically acceptable excipients suitable for inclusion in the pharmaceutical composition (prior to freeze drying) according to the invention are buffer solutions (e.g. citrate, histidine or succinate containing salts in water), cryoprotectants (e.g. sucrose) , Trehalose), isotonic agents (eg sodium chloride), surfactants (eg polysorbate), and extenders (eg mannitol, glycine). Excipients used in lyophilized protein preparations are selected for their ability to prevent protein denaturation during storage as well as during the lyophilization process.
본 발명은 추가적으로 약제로서 사용하기 위한 앞서 기재된 항-SIRPα 항체 또는 약학 조성물에 관한 것이다.The present invention further relates to the anti-SIRPα antibodies or pharmaceutical compositions described above for use as medicaments.
일 실시양태에서, 본 발명은 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 앞서 기재된 항-SIRPα 항체 또는 약학 조성물에 관한 것이다. 본 발명의 항-SIRPα 항체는 고형 종양, 예컨대 유방암, 신장암, 또는 흑색종, 또는 혈액 악성 종양, 예컨대 급성 골수성 백혈병(AML)의 치료에 사용될 수 있다. In one embodiment, the present invention relates to the anti-SIRPα antibody or pharmaceutical composition described above for use in the treatment of human solid tumors and hematologic malignancies. Anti-SIRPα antibodies of the invention can be used for the treatment of solid tumors such as breast cancer, kidney cancer, or melanoma, or hematologic malignancies such as acute myeloid leukemia (AML).
제2 실시양태에서, 본 발명은 SIRPα-양성 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 인간 면역 이펙터 세포에 존재하는 활성화 Fc 수용체에 결합하는 Fc 영역을 포함하는 항-SIRPα 항체에 관한 것이다. 바람직하게는, 인간 면역 이펙터 세포에 존재하는 활성화 Fc 수용체에 결합하는 Fc 영역은 IgA 또는 IgG 이소타입의 것이다. IgG1, IgG2, IgG3 또는 IgG4 이소타입의 Fc 영역을 포함하는 항-SIRPα 항체가 더 바람직하고; IgG1, IgG2 또는 IgG4 이소타입이 더욱 더 바람직하다. SIRPα-양성 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 IgG1 이소타입의 Fc 영역을 포함하는 항-SIRPα 항체가 가장 바람직하다.In a second embodiment, the present invention relates to an anti-SIRPα antibody comprising an Fc region that binds to an activating Fc receptor present in human immune effector cells for use in the treatment of SIRPα-positive human solid tumors and hematologic malignancies. . Preferably, the Fc region that binds to the activating Fc receptor present in human immune effector cells is of the IgA or IgG isotype. IgG 1 , IgG 2 , IgG 3 or More preferred are anti-SIRPα antibodies comprising an Fc region of an IgG 4 isotype; IgG 1 , IgG 2 or Even more preferred is the IgG 4 isotype. Most preferred are anti-SIRPα antibodies comprising an Fc region of IgG 1 isotype for use in the treatment of SIRPα-positive human solid tumors and hematologic malignancies.
제3 실시양태에서, 본 발명은 하나 이상의 다른 항암 요법의 사용과 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 앞서 기재된 항-SIRPα 항체 또는 약학 조성물에 관한 것이다. 적합한 항암 요법은 수술, 화학요법, 방사선 요법, 호르몬 요법, 표적 요법 및 면역요법이다. 앞서 기재된 항-SIRPα 항체 또는 약학 조성물은 인간 고형 종양 및 혈액 악성 종양의 치료에 있어 하나 이상의 다른 항암 요법의 사용과 조합하여 동시 또는 순차 사용을 위한 것일 수 있다. 특히, 앞서 기재된 항-SIRPα 항체 또는 약학 조성물은 하나 이상의 다른 항암 요법의 사용 이후에 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 것일 수 있다.In a third embodiment, the present invention relates to the anti-SIRPα antibody or pharmaceutical composition described above for use in the treatment of human solid tumors and hematologic malignancies in combination with the use of one or more other anticancer therapies. Suitable anticancer therapies are surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy and immunotherapy. The anti-SIRPα antibodies or pharmaceutical compositions described above may be for simultaneous or sequential use in combination with the use of one or more other anticancer therapies in the treatment of human solid tumors and hematologic malignancies. In particular, the anti-SIRPα antibodies or pharmaceutical compositions described above may be for use in the treatment of human solid tumors and hematologic malignancies following the use of one or more other anticancer therapies.
바람직하게는, 본 발명은 하나 이상의 다른 항암 치료제의 사용과 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 앞서 기재된 항-SIRPα 항체 또는 약학 조성물에 관한 것이다. 특히, 앞서 기재된 항-SIRPα 항체 또는 약학 조성물은 하나 이상의 다른 항암 치료제의 사용 이후에 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 것일 수 있다.Preferably, the present invention relates to the anti-SIRPα antibodies or pharmaceutical compositions described above for use in the treatment of human solid tumors and hematologic malignancies in combination with the use of one or more other anticancer therapeutic agents. In particular, the anti-SIRPα antibodies or pharmaceutical compositions described above may be for use in the treatment of human solid tumors and hematologic malignancies following the use of one or more other anticancer therapeutic agents.
적합한 항암 치료제는 화학 치료제, 방사선 치료제, 호르몬 치료제, 표적 치료제 및 면역치료제를 포함한다. 적합한 화학 치료제는 알킬화제, 예컨대 질소 머스터드, 니트로소우레아, 테트라진 및 아지리딘; 항대사산물, 예컨대 항-폴레이트, 플루오로피리미딘, 데옥시뉴클레오시드 유사체 및 티오퓨린; 항미세소관제, 예컨대 빈카 알칼로이드 및 탁산; 토포이소머라제 I 및 II 저해제; 및 세포독성 항생제, 예컨대 안트라사이클린 및 블레오마이신을 포함한다.Suitable anticancer therapies include chemotherapeutic agents, radiation therapies, hormone therapies, targeted therapies and immunotherapeutics. Suitable chemotherapeutic agents include alkylating agents, such as nitrogen mustards, nitrosoureas, tetrazin and aziridine; Anti metabolites such as anti-folates, fluoropyrimidines, deoxynucleoside analogs and thiopurines; Antimicrotubules such as vinca alkaloids and taxanes; Topoisomerase I and II inhibitors; And cytotoxic antibiotics such as anthracyclines and bleomycin.
적합한 방사선 치료제는 방사성 동위원소, 예컨대 131I-메타요오도벤질구아니딘(MIBG), 소듐 포스페이트로서 32P, 223Ra 클로라이드, 89Sr 클로라이드 및 153Sm 디아민 테트라메틸렌 포스포네이트(EDTMP)를 포함한다.Suitable radiotherapeutic agents include radioisotopes such as 131 I-Methiodobenzylguanidine (MIBG), 32 P, 223 Ra chloride, 89 Sr chloride and 153 Sm diamine tetramethylene phosphonate (EDTMP) as sodium phosphate.
호르몬 치료제로서 사용하기에 적합한 작용제는 호르몬 합성의 저해제, 예컨대 아로마타제 저해제 및 GnRH 유사체; 및 호르몬 수용체 길항체, 예컨대 선택적 에스트로겐 수용체 조절제 및 항안드로겐을 포함한다.Suitable agents for use as hormone therapy include inhibitors of hormone synthesis such as aromatase inhibitors and GnRH analogs; And hormone receptor antagonists such as selective estrogen receptor modulators and antiandrogens.
표적 치료제는 종양형성 및 증식에 수반되는 특정 단백질을 방해하는 치료제이며 소분자 약물; 단백질, 예컨대 치료용 항체; 펩티드 및 펩티드 유도체; 또는 단백질-소분자 하이브리드, 예컨대 항체-약물 접합체일 수 있다. 표적 소분자 약물의 예는 mTor 저해제, 예컨대 에베롤리무스, 템시롤리무스 및 라파마이신; 키나제 저해제, 예컨대 이매티닙, 다사티닙 및 닐로티닙; VEGF 저해제, 예컨대 소라페닙 및 레고라페닙; 및 EGFR/HER2 저해제 예컨대 제피티닙, 라파티닙 및 에를로티닙을 포함한다. 펩티드 또는 펩티드 유도체 표적 치료제의 예는 프로테아좀 저해제, 예컨대 보르테조밉 및 카르필조밉을 포함한다. Targeted therapeutic agents are therapeutic agents that interfere with specific proteins involved in tumorigenesis and proliferation and are small molecule drugs; Proteins such as therapeutic antibodies; Peptides and peptide derivatives; Or protein-small molecule hybrids, such as antibody-drug conjugates. Examples of target small molecule drugs include mTor inhibitors such as everolimus, temsirolimus and rapamycin; Kinase inhibitors such as imatinib, dasatinib, and nilotinib; VEGF inhibitors such as sorafenib and legorafenib; And EGFR / HER2 inhibitors such as zefitinib, lapatinib and erlotinib. Examples of peptide or peptide derivative targeted therapeutics include proteasome inhibitors such as bortezomib and carfilzomib.
면역치료제는 면역 반응을 유도, 향상 또는 억제하는 작용제, 예컨대 사이토카인(IL-2 및 IFN-α); 면역 조절성 이미드 약물, 예컨대 탈리도마이드, 레날리도마이드 및 포말리도마이드; 치료용 암 백신, 예컨대 탈리모겐 라허파렙벡; 세포 기반 면역치료제, 예컨대 수지상 세포 백신, 입양 T-세포 및 키메라 항원 수용체-변경된 T-세포); 및 암 세포상의 막 결합 리간드에 결합할 때 그 Fc 영역을 통해 ADCC/ADCP 또는 CDC를 촉발할 수 있는 치료용 항체를 포함한다.Immunotherapeutic agents include agents that induce, enhance or inhibit an immune response, such as cytokines (IL-2 and IFN-α); Immunomodulatory imide drugs such as thalidomide, lenalidomide and pomalidomide; Therapeutic cancer vaccines, such as Talimogen Laherparebbec; Cell based immunotherapeutics such as dendritic cell vaccines, adoptive T-cells and chimeric antigen receptor-modified T-cells); And therapeutic antibodies capable of triggering ADCC / ADCP or CDC via its Fc region when bound to a membrane binding ligand on cancer cells.
바람직하게는, 본 발명은 하나 이상의 다른 항암 치료제와 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 앞서 기재된 항-SIRPα 항체 또는 약학 조성물로서, 항암 치료제가 표적 치료제 또는 면역치료제인 항-SIRPα 항체 또는 약학 조성물에 관한 것이다. 본 발명에 따른 바람직한 표적 치료제는 치료용 항체 또는 항체-약물 접합체(ADC)이다. 가장 바람직한 표적 치료제는 치료용 항체이다.Preferably, the present invention provides an anti-SIRPα antibody or pharmaceutical composition as described above for use in the treatment of human solid tumors and hematologic malignancies in combination with one or more other anticancer therapeutic agents, wherein the anti-cancer therapeutic agent is a targeted therapeutic or immunotherapy. SIRPα antibodies or pharmaceutical compositions. Preferred target therapeutic agents according to the invention are therapeutic antibodies or antibody-drug conjugates (ADCs). Most preferred target therapeutic agents are therapeutic antibodies.
본 명세서 전반에 걸쳐 사용되는 용어 "치료용 항체"는 인간 요법에 적합한 앞서 정의된 항체 또는 이의 항원 결합 단편을 지칭한다. 인간 요법에 적합한 항체는 특정 인간 질환의 치료에 충분한 품질, 안전성 및 효능을 갖는다. 품질은 우수 제조 관리 기준(Good Manufacturing Practice)에 대해 확립된 지침을 사용하여 평가될 수 있고; 안전성과 효능은 일반적으로 의약품 규제 당국, 예를 들어, 유럽 의약품국(EMA) 또는 미국 식품 의약국(FDA)의 확립된 지침을 사용하여 평가된다. 이들 지침은 당업계에 익히 알려져 있다.The term “therapeutic antibody” as used throughout this specification refers to an antibody or antigen binding fragment thereof as defined above that is suitable for human therapy. Antibodies suitable for human therapy have sufficient quality, safety and efficacy for the treatment of certain human diseases. Quality can be assessed using established guidelines for Good Manufacturing Practices; Safety and efficacy are generally assessed using established guidelines from drug regulatory authorities, such as the European Drug Administration (EMA) or the US Food and Drug Administration (FDA). These guidelines are well known in the art.
바람직하게는, 치료용 항체는 의약품 규제 당국, 예컨대 EMA 또는 FDA에 의해 승인된 항체이다. 대부분의 규제 당국의 온라인 데이터베이스를 참조하여 항체 승인 여부를 확인할 수 있다.Preferably, the therapeutic antibody is an antibody approved by pharmaceutical regulatory authorities such as the EMA or FDA. Most regulatory authorities' online databases can be consulted for antibody approval.
본 명세서 전반에 걸쳐 사용되는 용어 "ADC"는 링커를 통해 앞서 정의된 항체 또는 이의 항원 결합 단편에 접합된 세포독성 약물을 지칭한다. 전형적으로, 세포독성 약물은 매우 강력한, 예를 들어 듀오카르마이신, 칼리케아미신, 피롤로벤조디아제핀(PBD) 이량체, 메이탄시노이드 또는 아우리스타틴 유도체이다. 링커는 절단 가능한, 예를 들어 절단성 디펩티드 발린-시트룰린(vc) 또는 발린-알라닌(va)을 포함할 수 있거나, 또는 비-절단성, 예를 들어 숙신이미딜-4-(N-말레이미도메틸)시클로헥산-1-카르복실레이트(SMCC)일 수 있다. The term "ADC" as used throughout this specification refers to a cytotoxic drug conjugated to a previously defined antibody or antigen binding fragment thereof via a linker. Typically, cytotoxic drugs are very potent, for example duocarmycin, calicheamicin, pyrrolobenzodiazepine (PBD) dimers, maytansinoids or auristatin derivatives. The linker may comprise cleavable, for example cleavable dipeptides valine-citrulline (vc) or valine-alanine (va), or non-cleavable, eg succinimidyl-4- (N-maleic Midomethyl) cyclohexane-1-carboxylate (SMCC).
전형적으로, 본 발명에 따른 항-SIRPα 항체와 조합하여 사용하기 위한 치료용 항체는, 아넥신 Al, B7H3, B7H4, CA6, CA9, CA15-3, CA19-9, CA27-29, CA125, CA242, CCR2, CCR5, CD2, CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD40, CD44, CD47, CD56, CD70, CD74, CD79, CD115, CD123, CD138, CD203c, CD303, CD333, CEA, CEACAM, CLCA-1, CLL-1, c-MET, 크립토(Cripto), CTLA-4, DLL3, EGFL, EGFR, EPCAM, EPh (예를 들어 EphA2 또는 EPhB3), 엔도텔린 B 수용체 (ETBR), FAP, FcRL5 (CD307), FGF, FGFR (예를 들어 FGFR3), FOLR1, GCC, GPNMB, HER2, HMW-MAA, 인테그린 α(예를 들어 αvβ3 및 αvβ5), IGF1R, TM4SF1 (또는 L6 항원), 루이스(Lewis) A 유사 카보하이드레이트, 루이스 X, 루이스 Y, LIV1, 메소텔린, MUC1, MUC16, NaPi2b, Nectin-4, PD-1, PD-L1, PSMA, PTK7, SLC44A4, STEAP-1, 5T4 항원 (또는 TPBG, 영양막 당단백질), TF (조직 인자), 톰슨 프라이덴리히(Thomsen-Friedenreich) 항원 (TF-Ag), Tag72, TNF, TNFR, TROP2, VEGF, VEGFR, 및 VLA로 이루어진 군에서 선택되는 표적에 결합하는 적어도 하나의 HCVR 및 LCVR을 포함하는 단일특이적 또는 이중특이적 항체 또는 항체 단편이다. Typically, therapeutic antibodies for use in combination with anti-SIRPα antibodies according to the present invention are annexin Al, B7H3, B7H4, CA6, CA9, CA15-3, CA19-9, CA27-29, CA125, CA242, CCR2, CCR5, CD2, CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD40, CD44, CD47, CD56, CD70, CD74, CD79, CD115, CD123, CD138, CD203c, CD303, CD333, CEA, CEACAM, CLCA-1, CLL-1, c-MET, Crypto, CTLA-4, DLL3, EGFL, EGFR, EPCAM, EPh (e.g. EphA2 or EPhB3), endothelin B receptor (ETBR), FAP, FcRL5 (CD307), FGF, FGFR (eg FGFR3), FOLR1, GCC, GPNMB, HER2, HMW-MAA, Integrin α (eg αvβ3 and αvβ5), IGF1R, TM4SF1 (or L6 antigen), Lewis A-like carbohydrate, Lewis X, Lewis Y, LIV1, mesothelin, MUC1, MUC16, NaPi2b, Nectin-4, PD-1, PD-L1, PSMA, PTK7, SLC44A4, STEAP-1, 5T4 antigen (or TPBG, Trophoblast glycoprotein), TF (tissue factor), Thomsen-Friedenreich antigen (TF-Ag), Tag72, TNF, TNFR, TROP2, VEGF, Monospecific or bispecific antibodies or antibody fragments comprising at least one HCVR and LCVR that bind to a target selected from the group consisting of VEGFR, and VLA.
단일특이적 치료용 항체가 바람직하다. 종양 세포의 표면 상의 막-결합 표적에 대한 항체가 보다 바람직하다.Monospecific therapeutic antibodies are preferred. More preferred are antibodies against membrane-bound targets on the surface of tumor cells.
본 발명에 따른 항-SIRPα 항체와 조합하여 사용하기 적합한 치료용 항체는 알렘투주맙, 베바시주맙, 세툭시맙, 파니투무맙, 리툭시맙, 및 트라스투주맙을 포함한다.Suitable therapeutic antibodies for use in combination with anti-SIRPα antibodies according to the present invention include alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, and trastuzumab.
본 발명에 따른 항-SIRPα 항체와 조합하여 사용하기 적합한 ADC는 트라스투주맙 엠탄신 및 브렌툭시맙 베도틴을 포함한다.Suitable ADCs for use in combination with anti-SIRPα antibodies according to the present invention include trastuzumab emtansine and brentuximab bedotin.
바람직한 실시양태에서, 본 발명은 인간 면역 이펙터 세포 상에 존재하는 활성화 Fc 수용체에 결합하는 인간 Fc 영역을 포함하는 종양 세포의 표면 상의 막-결합 표적에 대한 치료용 항체와 조합하여 앞서 언급한 사용을 위한 앞서 기재된 항-SIRPα 항체에 관한 것이다. In a preferred embodiment, the present invention uses the aforementioned use in combination with a therapeutic antibody against a membrane-bound target on the surface of a tumor cell comprising a human Fc region that binds to an activating Fc receptor present on human immune effector cells. It relates to the anti-SIRPα antibody described above for.
앞서 기재한 바와 같이 이들 활성화 Fc 수용체에의 결합을 통해, 인간 면역 이펙터 세포 상에 존재하는 활성화 Fc 수용체에 결합하는 인간 Fc 영역을 포함하는 치료용 항체는 ADCC 및/또는 ADCP를 유도할 수 있다. 인간 IgG, IgE, 또는 IgA 이소타입의 치료용 항체는 인간 면역 이펙터 세포 상에 존재하는 활성화 Fc 수용체에 결합하는 인간 Fc 영역을 포함한다.Through the binding to these activating Fc receptors as described above, therapeutic antibodies comprising human Fc regions that bind to activating Fc receptors present on human immune effector cells can induce ADCC and / or ADCP. Therapeutic antibodies of human IgG, IgE, or IgA isotypes comprise human Fc regions that bind to activating Fc receptors present on human immune effector cells.
본 발명에 따른 사용에 바람직한 치료용 항체는 IgG 또는 IgA 이소타입의 치료용 항체이다. IgG 이소타입, 예컨대 IgG1, IgG2, IgG3, 및 IgG4 항체의 치료용 항체가 보다 바람직하다. IgG1 또는 IgG2 이소타입의 치료용 항체가 더욱 더 바람직하다. IgG1 이소타입의 치료용 항체가 가장 바람직하다. Preferred therapeutic antibodies for use according to the invention are therapeutic antibodies of the IgG or IgA isotype. More preferred are therapeutic antibodies for IgG isotypes such as IgG 1 , IgG 2 , IgG 3 , and IgG 4 antibodies. IgG 1 or Even more preferred are therapeutic antibodies of the IgG 2 isotype. Most preferred are therapeutic antibodies of the IgG 1 isotype.
바람직하게는, 본 발명은, 인간 면역 이펙터 세포 상에 존재하는 활성화 Fc 수용체에 결합하는 인간 Fc 영역을 포함하는 종양 세포의 표면 상의 막-결합 표적에 대한 치료용 항체의 사용과 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한, Preferably, the present invention is a human solid tumor in combination with the use of a therapeutic antibody against a membrane-bound target on the surface of a tumor cell comprising a human Fc region that binds to an activating Fc receptor present on human immune effector cells. And for use in the treatment of hematologic malignancies,
a. 서열 번호 1의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 2의 CDR1, CDR2 및 CDR3 아미노산 서열; a. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 1 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 2;
b. 서열 번호 3의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 4의 CDR1, CDR2 및 CDR3 아미노산 서열;b. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 3 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 4;
c. 서열 번호 5의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 6의 CDR1, CDR2 및 CDR3 아미노산 서열;c. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 5 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 6;
d. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열;d. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8;
e. 서열 번호 9의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 10의 CDR1, CDR2 및 CDR3 아미노산 서열;e. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 9 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 10;
f. 서열 번호 11의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 12의 CDR1, CDR2 및 CDR3 아미노산 서열;f. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 11 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 12;
g. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열;g. The CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13 and the CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14;
h. 서열 번호 15의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 16의 CDR1, CDR2 및 CDR3 아미노산 서열; 및h. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 15 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 16; And
i. 서열 번호 17의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 18의 CDR1, CDR2 및 CDR3 아미노산 서열i. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 17 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 18
로 이루어진 군에서 선택되는 HCVR 및 LCVR CDR을 포함하는 인간화 항-SIRPα 항체에 관한 것으로, 여기서 항-SIRPα 항체는 야생형 Fc 영역을 포함하는 동일한 항-SIRPα 항체와 비교하여 인간 Fcα 또는 Fcγ 수용체에 대한 감소된 결합을 나타내는 변경된 Fc 영역을 포함한다.A humanized anti-SIRPα antibody comprising HCVR and LCVR CDRs selected from the group consisting of: wherein the anti-SIRPα antibody is reduced against human Fcα or Fcγ receptors as compared to the same anti-SIRPα antibody comprising a wild type Fc region It includes an altered Fc region that represents the binding.
바람직한 실시양태에서, 치료용 항체와 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 인간화 항-SIRPα 항체는, L234, L235, G237, D265, D270, N297, A327, P328, 및 P329(Eu 넘버링)로 이루어진 군에서 선택되는 하나 이상의 위치에서 하나 이상의 아미노산 치환을 포함하는 변경된 인간 IgG1 Fc 영역을 포함한다. In a preferred embodiment, humanized anti-SIRPα antibodies for use in the treatment of human solid tumors and hematologic malignancies in combination with therapeutic antibodies comprise L234, L235, G237, D265, D270, N297, A327, P328, and P329 ( Eu numbering), comprising an altered human IgG 1 Fc region comprising one or more amino acid substitutions at one or more positions selected from the group consisting of:
바람직하게는, 치료용 항체와 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 인간화 항-SIRPα 항체는, 아미노산 치환 N297A 또는 N297G를 포함하지 않는 변경된 Fc IgG1 영역을 포함한다. 더 바람직하게는, 항-SIRPα 항체는, 위치 N297에서 아미노산 치환을 포함하지 않는 변경된 Fc IgG1 영역을 포함한다.Preferably, the humanized anti-SIRPα antibody for use in the treatment of human solid tumors and hematologic malignancies in combination with a therapeutic antibody comprises an altered Fc IgG 1 region that does not comprise amino acid substitutions N297A or N297G. More preferably, the anti-SIRPα antibody comprises an altered Fc IgG 1 region that does not comprise an amino acid substitution at position N297.
일 실시양태에서, 변경된 인간 IgG1 Fc 영역은 L234A, L234E, L235A, G237A, D265A, D265E, D265N, D270A, D270E, D270N, N297A, N297G, A327Q, P328A, P329A, 및 P329G로 이루어진 군에서 선택되는 하나 이상의 아미노산 치환을 포함한다.In one embodiment, the modified human IgG 1 Fc region is selected from the group consisting of L234A, L234E, L235A, G237A, D265A, D265E, D265N, D270A, D270E, D270N, N297A, N297G, A327Q, P328A, P329A, and P329G. One or more amino acid substitutions.
또 다른 실시양태에서, 치료용 항체와 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 인간화 항-SIRPα 항체는, L234A, L234E, L235A, G237A, D265A, D265E, D265N, D270A, D270E, D270N, A327Q, P328A, P329A 및 P329G로 이루어진 군에서 선택되는 하나 이상의 아미노산 치환을 포함하는 변경된 Fc IgG1 영역을 포함한다. 바람직하게는, 하나 이상의 아미노산 치환은 L234A, L234E, L235A, G237A, D265A, D265E, D265N, P328A, P329A 및 P329G로 이루어진 군에서 선택된다. 더 바람직하게는, 변경된 Fc IgG1 영역은 아미노산 치환 N297A 또는 N297G를 포함하지 않는다. 더욱 더 바람직하게는, 변경된 Fc IgG1 영역은 위치 N297에서 아미노산 치환을 포함하지 않는다.In another embodiment, humanized anti-SIRPα antibodies for use in the treatment of human solid tumors and hematologic malignancies in combination with therapeutic antibodies include L234A, L234E, L235A, G237A, D265A, D265E, D265N, D270A, D270E, An altered Fc IgG 1 region comprising one or more amino acid substitutions selected from the group consisting of D270N, A327Q, P328A, P329A and P329G. Preferably, at least one amino acid substitution is selected from the group consisting of L234A, L234E, L235A, G237A, D265A, D265E, D265N, P328A, P329A and P329G. More preferably, the altered Fc IgG 1 region does not comprise amino acid substitutions N297A or N297G. Even more preferably, the altered Fc IgG 1 region does not comprise an amino acid substitution at position N297.
바람직한 실시양태에서, 변경된 인간 IgG1 Fc 영역은 아미노산 치환 L234A 및 L235A, L234E 및 L235A, L234A, L235A 및 P329A 또는 L234A, L235A 및 P329G를 포함한다. 바람직하게는, 변경된 Fc IgG1 영역은 아미노산 치환 N297A 또는 N297G를 포함하지 않는다. 더 바람직하게는, 변경된 Fc IgG1 영역은 위치 N297에서 아미노산 치환을 포함하지 않는다.In a preferred embodiment, the modified human IgG 1 Fc region comprises amino acid substitutions L234A and L235A, L234E and L235A, L234A, L235A and P329A or L234A, L235A and P329G. Preferably, the altered Fc IgG 1 region does not comprise amino acid substitution N297A or N297G. More preferably, the altered Fc IgG 1 region does not comprise amino acid substitutions at position N297.
또 다른 바람직한 실시양태에서, 치료용 항체와 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 인간화 항-SIRPα 항체는, 아미노산 치환 L234A 및 L235A 또는 L234E 및 L235A, 바람직하게는 아미노산 치환 L234A 및 L235A를 포함하는 변경된 인간 IgG1 Fc 영역을 포함한다. 더 바람직하게는, 변경된 Fc IgG1 영역은 아미노산 치환 N297A 또는 N297G를 포함하지 않는다. 더욱 더 바람직하게는, 변경된 Fc IgG1 영역은 위치 N297에서 아미노산 치환을 포함하지 않는다.In another preferred embodiment, the humanized anti-SIRPα antibodies for use in the treatment of human solid tumors and hematologic malignancies in combination with therapeutic antibodies comprise amino acid substitutions L234A and L235A or L234E and L235A, preferably amino acid substitutions L234A and An altered human IgG 1 Fc region comprising L235A. More preferably, the altered Fc IgG 1 region does not comprise amino acid substitutions N297A or N297G. Even more preferably, the altered Fc IgG 1 region does not comprise an amino acid substitution at position N297.
바람직한 실시양태에서, 인간 면역 이펙터 세포 상에 존재하는 활성화 Fc 수용체에 결합하는 인간 Fc 영역을 포함하는 종양 세포의 표면 상의 막-결합 표적에 대한 치료용 항체의 사용과 조합하여 인간 고형 종양 및 혈액 악성 종양의 치료에 사용하기 위한 인간화 항-SIRPα 항체는, 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역, 및 하기로 이루어진 군에서 선택되는 HCVR 및 LCVR CDR을 포함한다:In a preferred embodiment, human solid tumors and hematologic malignancies in combination with the use of therapeutic antibodies against membrane-bound targets on the surface of tumor cells comprising human Fc regions that bind to activating Fc receptors present on human immune effector cells. Humanized anti-SIRPα antibodies for use in the treatment of tumors comprise an Fc region comprising amino acid substitutions L234A and L235A, and HCVR and LCVR CDRs selected from the group consisting of:
a. 서열 번호 3의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 4의 CDR1, CDR2 및 CDR3 아미노산 서열; a. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 3 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 4;
b. 서열 번호 5의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 6의 CDR1, CDR2 및 CDR3 아미노산 서열; b. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 5 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 6;
c. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열;c. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8;
d. 서열 번호 9의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 10의 CDR1, CDR2 및 CDR3 아미노산 서열; 및d. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 9 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 10; And
e. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열.e. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 13 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 14.
제2의 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역, 및 하기로 이루어진 군에서 선택되는 HCVR 및 LCVR CDR을 포함한다:In a second preferred embodiment, the humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, and an HCVR and LCVR CDR selected from the group consisting of:
a. 서열 번호 5의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 6의 CDR1, CDR2 및 CDR3 아미노산 서열;a. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 5 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 6;
b. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열; 및b. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8; And
c. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열.c. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 13 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 14.
제3의 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역, 및 하기로 이루어진 군에서 선택되는 HCVR 및 LCVR CDR을 포함한다:In a third preferred embodiment, the humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, and an HCVR and LCVR CDR selected from the group consisting of:
a. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열; 및a. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8; And
b. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열.b. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 13 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 14.
제4의 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역, 및 이하의 것을 포함한다:In a fourth preferred embodiment, the humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, and the following:
a. 서열 번호 30의 HCVR 아미노산 서열 및 서열 번호 31의 LCVR 아미노산 서열;a. The HCVR amino acid sequence of SEQ ID NO: 30 and the LCVR amino acid sequence of SEQ ID NO: 31;
b. 서열 번호 32의 HCVR 아미노산 서열 및 서열 번호 33의 LCVR 아미노산 서열;b. The HCVR amino acid sequence of SEQ ID NO: 32 and the LCVR amino acid sequence of SEQ ID NO: 33;
c. 서열 번호 34의 HCVR 아미노산 서열 및 서열 번호 8의 LCVR 아미노산 서열;c. The HCVR amino acid sequence of SEQ ID NO: 34 and the LCVR amino acid sequence of SEQ ID NO: 8;
d. 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 36의 LCVR 아미노산 서열;d. The HCVR amino acid sequence of SEQ ID NO: 35 and the LCVR amino acid sequence of SEQ ID NO: 36;
e. 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열;e. The HCVR amino acid sequence of SEQ ID NO: 35 and the LCVR amino acid sequence of SEQ ID NO: 37;
f. 서열 번호 13의 HCVR 아미노산 서열 및 서열 번호 38의 LCVR 아미노산 서열; 또는f. The HCVR amino acid sequence of SEQ ID NO: 13 and the LCVR amino acid sequence of SEQ ID NO: 38; or
g. 서열 번호 13의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열.g. The HCVR amino acid sequence of SEQ ID NO: 13 and LCVR amino acid sequence of SEQ ID NO: 37.
일 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역과, 서열 번호 30의 HCVR 아미노산 서열 및 서열 번호 31의 LCVR 아미노산 서열을 포함한다. 더 바람직하게는, 변경된 Fc IgG1 영역은 아미노산 치환 N297A 또는 N297G를 포함하지 않는다. 더욱 더 바람직하게는, 변경된 Fc IgG1 영역은 위치 N297에서 아미노산 치환을 포함하지 않는다.In one preferred embodiment, a humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, an HCVR amino acid sequence of SEQ ID NO: 30 and an LCVR amino acid sequence of SEQ ID NO: 31 . More preferably, the altered Fc IgG 1 region does not comprise amino acid substitutions N297A or N297G. Even more preferably, the altered Fc IgG 1 region does not comprise an amino acid substitution at position N297.
또 다른 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역과, 서열 번호 32의 HCVR 아미노산 서열 및 서열 번호 33의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, a humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, an HCVR amino acid sequence of SEQ ID NO: 32 and an LCVR amino acid sequence of SEQ ID NO: 33 do.
또 다른 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역과, 서열 번호 34의 HCVR 아미노산 서열 및 서열 번호 8의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, a humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, an HCVR amino acid sequence of SEQ ID NO: 34 and an LCVR amino acid sequence of SEQ ID NO: 8 do.
또 다른 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역과, 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 36의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, a humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, an HCVR amino acid sequence of SEQ ID NO: 35 and an LCVR amino acid sequence of SEQ ID NO: 36 do.
또 다른 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역과, 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, a humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, an HCVR amino acid sequence of SEQ ID NO: 35 and an LCVR amino acid sequence of SEQ ID NO: 37 do.
또 다른 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역과, 서열 번호 13의 HCVR 아미노산 서열 및 서열 번호 38의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, a humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, an HCVR amino acid sequence of SEQ ID NO: 13 and an LCVR amino acid sequence of SEQ ID NO: 38 do.
또 다른 바람직한 실시양태에서, 앞서 정의된 바와 같이 사용하기 위한 인간화 항-SIRPα 항체는 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역과, 서열 번호 13의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열을 포함한다.In another preferred embodiment, a humanized anti-SIRPα antibody for use as defined above comprises an Fc region comprising amino acid substitutions L234A and L235A, an HCVR amino acid sequence of SEQ ID NO: 13 and an LCVR amino acid sequence of SEQ ID NO: 37 do.
더 바람직하게는, 아미노산 치환 L234A 및 L235A를 포함하는 Fc 영역을 포함하는 앞서 정의된 바와 같이 사용하기 위한 앞서 정의된 인간화 항-SIRPα 항체는, 변경된 Fc IgG1 영역이 아미노산 치환 N297A 또는 N297G를 포함하지 않는다. 더욱 더 바람직하게는, 변경된 Fc IgG1 영역은 위치 N297에서 아미노산 치환을 포함하지 않는다.More preferably, the previously defined humanized anti-SIRPα antibody for use as defined above comprising an Fc region comprising amino acid substitutions L234A and L235A, wherein the altered Fc IgG 1 region does not comprise amino acid substitution N297A or N297G. Do not. Even more preferably, the altered Fc IgG 1 region does not comprise an amino acid substitution at position N297.
앞서 기재된 바와 같이 야생형 Fc 영역을 포함하는 동일한 항-SIRPα 항체와 비교했을 때 인간 Fcα 또는 Fcγ 수용체에 대해 감소된 결합을 나타내는 변경된 Fc 영역을 포함하는 항-SIRPα 항체는 SIRPαBIT 또는 SIRPα1에 대해 동형 접합성의 상이한 도너로부터의 이펙터 세포로서 호중구를 사용하여 치료용 항체의 시험관내 ADCC를 향상시킨다. 이들 항체 모두가 대부분의 도너의 호중구를 사용하여 시험관내 ADCC를 증가시키며, 바람직한 항체는 심지어 모든 도너의 호중구를 사용하여 시험관내 ADCC를 증가시킨다.An anti-SIRPα antibody comprising an altered Fc region exhibiting reduced binding to human Fcα or Fcγ receptors when compared to the same anti-SIRPα antibody comprising a wild type Fc region, as described above, may be selected from SIRPα BIT or Neutrophils are used as effector cells from different donors homozygous for SIRPα 1 to enhance in vitro ADCC of the therapeutic antibody. All of these antibodies increase the in vitro ADCC using most of the donors 'neutrophils, while the preferred antibody even increases the in vitro ADCC using all the donors' neutrophils.
실시예Example
면역화 프로토콜 및 선택Immunization Protocols and Selection
토끼를 인간 (hu)SIRPαBIT, 인간 (hu)SIRPα1 및 시노몰구스 (cy)SIRPα의 세포외 도메인 영역을 나타내는 펩티드들의 혼합물로 반복적으로 면역화시켰다. 혈액을 다른 시점에 수집하고 림프구로 농축시켰다. 단일 B-세포를 마이크로타이터 플레이트의 단일 웰에 넣었다. 이들 B-세포를 조건화된 배지 및 피더 세포의 존재하에 며칠 동안 배양하였다. 이 기간 동안 이들은 모노클로날 항체를 생산하여 배양 배지(B-세포 상청액)에 방출했다. 이들 단일 B-세포의 상청액을 IgG 생산에 대해 분석했으며; 이후에 cySIRPα 및 항-Fc 항체에 대한 huSIRPαBIT 및 huSIRPα1의 특이적 결합을 확인하였다. 적합한 상청액은 huSIRPαBIT 및 huSIRPα1 둘 다, 및 cySIRPα에 결합하는 것들이었다. 히트 피킹(hit picking) 단계 이후에 마우스 (mu) SIRPα 및 huSIRPβ1v1, huSIRPβ1v2 및 huSIRPγ(항-표적으로서)에 대한 결합을 측정했다. 부가적으로, SIRPαBIT 및 SIRPα1-과발현 CHO 세포에 대한 결합을 확인했다. 모체 CHO 세포에 대한 결합을 대조군 어세이로서 적용했다.Rabbits were human (hu) SIRPα BIT , human (hu) SIRPα 1 and Immunization was repeated with a mixture of peptides representing the extracellular domain region of cynomolgus (cy) SIRPα. Blood was collected at different time points and concentrated into lymphocytes. Single B-cells were placed in a single well of a microtiter plate. These B-cells were incubated for several days in the presence of conditioned medium and feeder cells. During this time they produced monoclonal antibodies and released them into the culture medium (B-cell supernatant). Supernatants of these single B-cells were analyzed for IgG production; Thereafter, specific binding of huSIRPα BIT and huSIRPα 1 to cySIRPα and anti-Fc antibodies was confirmed. Suitable supernatants are huSIRPα BIT and both huSIRPα 1 and those that bind cySIRPα. After the hit picking step, the mice (mu) SIRPα and huSIRPβ 1v1 , huSIRPβ 1v2 and Binding to huSIRPγ (as anti-target) was measured. In addition, SIRPα BIT and Binding to SIRPα 1 -overexpressing CHO cells was confirmed. Binding to parental CHO cells was applied as a control assay.
RNA 단리, 역전사 및 서열 분석을 위해 적합한 B-세포 용해물을 선택했다. 항체 경쇄 및 중쇄의 독특한 가변 영역을 유전자 합성하고 각각 항체 불변 영역 서열(카파 LC 서열 번호 26 및 인간 IgG1 HC-LALA 포맷 서열 번호 27) 앞에서 클로닝 하였다. Suitable B-cell lysates were selected for RNA isolation, reverse transcription and sequencing. Unique variable regions of the antibody light and heavy chains were gene synthesized and cloned before the antibody constant region sequences (kappa LC SEQ ID NO 26 and human IgG 1 HC-LALA format SEQ ID NO 27), respectively.
HEK 293 세포를 Tecan Freedom Evo 플랫폼에서 자동화된 절차를 사용하여 항체 서열 함유 플라스미드로 일시적으로 형질감염시켰다. 플레이트 오토샘플러를 갖는 Dionex Ultimate 3000 HPLC 시스템에서 친화성 정제(단백질 A)를 사용하여 세포 상청액으로부터 면역글로불린을 정제했다. 생산된 항체를 ELISA-타입 어세이(ELISA: huSIRPα1, huSIRPαBIT, cySIRPα, muSIRPα, huSIRPβ1v1/β1v2/γ; 세포 결합 어세이: huSIRPα1, huSIRPαBIT)에서 시험했다.HEK 293 cells were transiently transfected with antibody sequence containing plasmids using an automated procedure on the Tecan Freedom Evo platform. Immunoglobulins were purified from cell supernatants using affinity purification (Protein A) in a Dionex Ultimate 3000 HPLC system with a plate autosampler. The antibodies produced were tested in ELISA-type assays (ELISA: huSIRPα 1 , huSIRPα BIT , cySIRPα, muSIRPα, huSIRPβ 1v1 / β 1v2 / γ; cell binding assays: huSIRPα 1 , huSIRPα BIT ).
항체의 일시적 발현Transient expression of antibodies
a)a) cDNA 구성체 및 발현 벡터의 제조Preparation of cDNA Constructs and Expression Vectors
항체의 HCVR 아미노산 서열을 각각 N-말단에서 리더 서열(항체 1-9, 15, 16의 경우 서열 번호 28; 항체 10-14의 경우 서열 번호 39)에 결합시키고, C-말단에서 서열 번호 27에 따른 인간 IgG1 HC LALA의 불변 도메인에 결합시켰다. 항체 12C4huIgG1LALA, 12C4huIgG1 또는 29AM4-5huIgG1LALA의 HCVR 아미노산 서열을 각각 N-말단에서 HAVT20 리더 서열(서열 번호 29)에 결합시키고 C-말단에서 서열 번호 27에 따른 인간 IgG1 HC LALA 또는 야생형 인간 IgG1 HC(서열 번호 25)의 불변 도메인에 결합시켰다. 생성된 키메라 아미노산 서열을 인간 세포(호모 사피엔스)에서의 발현을 위해 코돈-최적화된 cDNA 서열로 역번역시켰다. 마찬가지로, 상기 구성체의 LC에 대한 키메라 cDNA 서열은, 리더 서열의 서열들(항체 1-9, 12의 경우 서열 번호 28; 항체 10, 11, 13-16의 경우 서열 번호 40, 12C4huIgG1LALA, 12C4huIgG1 및 29AM4-5huIgG1LALA의 경우 서열 번호 29)을 N-말단에서 항체 1-16, 12C4huIgG1LALA 및 12C4huIgG1 및 29AM4-5huIgG1LALA의 LCVR에 그리고 C-말단에서 인간 IgG1 κ 경쇄 불변 영역(서열 번호 26)에 결합시킴으로써 수득되었다. 표 1에 따른 HCVR 및 LCVR 서열을 사용하였다.The HCVR amino acid sequence of the antibody is linked to the leader sequence at the N-terminus (SEQ ID NO 28 for antibodies 1-9, 15, 16; SEQ ID NO: 39 for antibody 10-14), and at SEQ ID NO: 27 at the C-terminal end According to the constant domain of human IgG 1 HC LALA. Antibody 12C4huIgG 1 LALA, 12C4huIgG 1 or The HCVR amino acid sequence of 29 AM4-5huIgG 1 LALA is respectively linked to the HAVT20 leader sequence (SEQ ID NO: 29) at the N-terminus and human IgG 1 HC LALA or wild type human IgG 1 HC (SEQ ID NO: 25) according to SEQ ID NO: 27 at the C-terminus Bound to the constant domain. The resulting chimeric amino acid sequence was reverse translated into codon-optimized cDNA sequence for expression in human cells (Homo sapiens). Likewise, the chimeric cDNA sequence for the LC of the construct is the sequence of the leader sequence (SEQ ID NO 28 for antibodies 1-9, 12; SEQ ID NO: 40 for
b)b) 벡터 구성 및 클로닝 전략Vector composition and cloning strategy
항체 쇄의 발현을 위해 CMV:BGHpA 발현 카세트를 함유하는 포유동물 발현 벡터를 사용하였다. HC 또는 LC 발현 카세트(각각 CMV:HC:BGHpA 및 CMV:LC-BGHpA)를 함유하는 최종 벡터를 이. 콜라이(E. coli) NEB 5-알파 세포로 옮기고 증식시켰다. 형질감염을 위한 최종 발현 벡터의 대규모 생산은 Maxi- 또는 Megaprep 키트(Qiagen)를 사용하여 수행되었다.Mammalian expression vectors containing the CMV: BGHpA expression cassette were used for expression of the antibody chains. Final vectors containing HC or LC expression cassettes (CMV: HC: BGHpA and CMV: LC-BGHpA, respectively) were obtained from E. coli. E. coli NEB 5-alpha cells were transferred and expanded. Large scale production of the final expression vector for transfection was performed using the Maxi- or Megaprep kit (Qiagen).
c)c) 포유동물 세포에서의 일시적 발현Transient expression in mammalian cells
시판되는 Expi293F 세포(Thermo Fisher)를 하기와 같이 제조사의 지시에 따라 ExpiFectamine 형질감염제를 사용하여 발현 벡터로 형질감염시켰다: 75x107 세포를 300 mL FortiCHO 배지에 시딩하고, 300 ㎍의 발현 벡터를 800 ㎕의 ExpiFectamine 형질감염제와 조합하여 세포에 첨가하였다. 형질감염 후 1일째, 1.5 ml 인핸서 1 및 15 ml 인핸서 2를 배양물에 첨가하였다. 형질감염 후 6일째, 세포 배양 상청액을 15분 동안 4,000g에서 원심분리하여 수확하고 정화된 수확물을 PES 병 필터/MF 75 필터(Nalgene)를 통해 여과하였다.Commercially available Expi293F cells (Thermo Fisher) were transfected with expression vectors using ExpiFectamine transfectants according to the manufacturer's instructions as follows: 75 × 10 7 cells were seeded in 300 mL FortiCHO medium and 300 μg of expression vector was 800 Cells were added in combination with μl of ExpiFectamine transfectant. One day after transfection, 1.5
항체 결합 및 특이성Antibody Binding and Specificity
실험Experiment
ELISA 어세이: 포스페이트 완충 식염(PBS) 중의 huSIRPα1, huSIRPαBIT, huSIRPβ1v1, huSIRPβ1v2, huSIRPγ 및 cySIRPα의 용액을 각각 ELISA를 위해 복수 웰 블랙 폴리스티렌 플레이트에 첨가하고 실온에서 1시간 동안 부착을 허용했다. 결합되지 않은 단백질은 표준 세척 버퍼를 사용하여 3단계 세척으로 제거했다. 이후, 블로킹 버퍼를 웰에 첨가했다. 실온에서 1시간 인큐베이션 후, 웰을 표준 세척 버퍼로 3회 세척했다. 각종 농도의 버퍼 중의 항체를 웰에 첨가하고 실온에서 1시간 동안 인큐베이션했다. 결합되지 않은 항체는 표준 세척 버퍼를 사용하여 3단계 세척으로 제거했다. 버퍼 중의 염소 항 인간 IgG (Fab')2:홀스 래디시 퍼옥시다제(HRP)를 웰에 첨가하고 실온에서 1시간 동안 인큐베이션했다. 3,3',5,5'-테트라메틸벤지딘(TMB)을 첨가하고 충분한 발색 후 HCl을 첨가했다. 450 nm/620 nm에서 흡광도를 판독했다. ELISA Assay: Solutions of huSIRPα 1 , huSIRPα BIT , huSIRPβ 1v1 , huSIRPβ 1v2 , huSIRPγ and cySIRPα in phosphate buffered saline (PBS), respectively, were added to multiple well black polystyrene plates for ELISA and allowed to attach for 1 hour at room temperature. . Unbound proteins were removed in a three step wash using a standard wash buffer. Thereafter, blocking buffer was added to the wells. After 1 hour incubation at room temperature, the wells were washed three times with standard wash buffer. Antibodies in various concentrations of buffer were added to the wells and incubated for 1 hour at room temperature. Unbound antibody was removed in a three step wash using a standard wash buffer. Goat anti human IgG (Fab ') 2 : horse radish peroxidase (HRP) in buffer was added to the wells and incubated for 1 hour at room temperature. 3,3 ', 5,5'-tetramethylbenzidine (TMB) was added and HCl was added after sufficient color development. Absorbance was read at 450 nm / 620 nm.
표면 플라스몬 공명(SPR) 어세이: 25℃에서 표면 플라스몬 공명 장치(Biacore T200 시스템, GE Life Sciences)에서 단일 사이클 동역학 분석에 의해 친화성 분석을 수행하였다. 10 ㎕/min에서 60초간 스트렙트아비딘 접합체(20x 희석된 비오틴 CAPture 시약, GE Life Sciences)의 주입 후 10 μL/min에서 60초간 런닝 버퍼(pH 7.4의 10 mM HEPES 버퍼, 150 mM NaCl, 3 mM EDTA 및 0.005% v/v 폴리옥시에틸렌 (20) 소르비탄 모노라우레이트(계면활성제 P20) 보유)에 5 ㎍/ml의 SIRP 항원을 주입함으로써 비오티닐화 SIRP 항원을 비오티닐화 분자에 적합한 칩(Sensor Chip CAP, GE Life Sciences)의 표면 상에 포획시켰다. 베이스라인 안정화를 1분으로 설정한 후 런닝 버퍼(pH 7.4의 10 mM HEPES 버퍼, 150 mM NaCl, 3 mM EDTA 및 0.005% v/v 폴리옥시에틸렌 (20) 소르비탄 모노라우레이트 보유)에서 5가지 증가 농도의 항-SIRP 항체를 주입했다. 각 단계에서, 모두 30 μL/min의 유속에서, 150초의 회합 시간을 사용했고, 이후, 최고 농도에서만 1200초의 해리 시간을 사용했다. 6 M 구아니딘-HCl, 0.25 M NaOH 용액(유속 30 μL/min으로 60초)으로 재생을 수행하였다. 비 항-SIRP(블랭크) 고정화 기준 흐름 채널 및 런닝 버퍼 주입을 사용하여 관찰된 센서그램에 대해 이중 블랭크 공제를 수행하였다. 센서그램에는 모든 시험된 항-SIRP 항체에 대해 1:1 랭뮤어 모델이 적합화되었다. 동역학 파라미터(ka, kd 및 KD)를 Biacore T200 평가 소프트웨어(v3.1)를 사용하여 계산했다. Surface Plasmon Resonance (SPR) Assay: Affinity analysis was performed by single cycle kinetic analysis at a surface plasmon resonance apparatus (Biacore T200 system, GE Life Sciences) at 25 ° C. Infusion of streptavidin conjugate (20 × diluted Biotin CAPture reagent, GE Life Sciences) for 60 seconds at 10 μl / min, followed by running buffer (pH 7.4, 10 mM HEPES buffer, pH 7.4, 150 mM NaCl, 3 mM for 60 seconds). Chips suitable for biotinylated molecules by injecting 5 μg / ml of SIRP antigen into EDTA and 0.005% v / v polyoxyethylene (20) sorbitan monolaurate with surfactant P20) Sensor Chip CAP, GE Life Sciences). Five sets of running buffer (10 mM HEPES buffer at pH 7.4, 150 mM NaCl, 3 mM EDTA and 0.005% v / v polyoxyethylene (20) sorbitan monolaurate) after baseline stabilization set to 1 minute Increasing concentrations of anti-SIRP antibody were injected. In each step, an association time of 150 seconds was used, all at a flow rate of 30 μL / min, after which a dissociation time of 1200 seconds was used only at the highest concentration. Regeneration was performed with 6 M guanidine-HCl, 0.25 M NaOH solution (60 sec at 30 μL / min flow rate). Double blank subtraction was performed on the observed sensorgrams using a non anti-SIRP (blank) immobilized reference flow channel and running buffer injection. Sensorgrams were fitted with a 1: 1 Langmuir model for all tested anti-SIRP antibodies. Kinematic parameters k a , k d and K D ) was calculated using Biacore T200 evaluation software (v3.1).
유세포 분석: 인간 SIRPαBIT 항원을 내생적으로 발현하는 U937 세포 및 인간 SIRPα1, SIRPαBIT 또는 cySIRPα항원을 발현하는 CHO-S 차이니즈 햄스터 난소 세포(ExpiCHO-S) 세포로부터 스크리닝 및 단리된 비조작된 서브클론에서 유래된 세포(96-웰 플레이트에서 100,000 세포/웰)를, 0.2% v/w BSA(Sigma-Aldrich, 미주리주 세인트루이스) 및 0.02% v/w NaN3(Sigma-Aldrich)를 함유한 빙냉 FACS 버퍼(1x PBS (LONZA))로 3회 세척하고, 이후에 빙냉 FACS 버퍼에서 희석된 소정 농도 범위의 각 일차 mAb(50 μL/웰)을 첨가했다. 4℃에서 30분의 인큐베이션 시간 후, 세포를 빙냉 FACS 버퍼로 3회 세척하고 50 μL/웰 이차 mAb(AffiniPure F(ab')2 단편 염소-항-인간 IgG-APC, 1:6,000 희석, Jackson Immuno Research)를 첨가했다. 4℃에서 30분 후, 세포를 2회 세척하고 150 μL FACS 버퍼에 재현탁시켰다. 형광 강도는 유세포 분석(BD FACSVerse, 뉴저지주 프랭클린 레이크스)에 의해 결정되었고 U937 세포 및 ExpiCHO-S 세포에 대한 중앙 형광 강도(MFI-Median)로서 표시되었다. GraphPad Prism(Windows의 경우 버전 7.02, GraphPad, 캘리포니아주 샌디에고)에서 가변 기울기(4개의 파라미터)를 갖는 시그모이드 용량-반응 방정식을 사용하여 비선형 회귀에 의해 곡선을 피팅하였다. EC50 값은 4-파라미터 로지스틱 피트(logistic fit)을 사용할 때 곡선의 하단과 상단의 중간의 반응을 제공하는 μg/mL의 농도로서 계산되었다. Flow cytometry: U937 cells endogenously expressing human SIRPα BIT antigen and human SIRPα 1 , SIRPα BIT or Cells derived from unengineered subclone screened and isolated from CHO-S Chinese hamster ovary cells (ExpiCHO-S) cells expressing cySIRPα antigen (100,000 cells / well in 96-well plates), 0.2% v / w Wash three times with ice cold FACS buffer (1 × PBS (LONZA)) containing BSA (Sigma-Aldrich, St. Louis, MO) and 0.02% v / w NaN 3 (Sigma-Aldrich) and then diluted in ice cold FACS buffer Each primary mAb (50 μL / well) in the predetermined concentration range was added. After a 30 min incubation time at 4 ° C., cells were washed three times with ice cold FACS buffer and 50 μL / well secondary mAb (AffiniPure F (ab ′) 2 fragment goat-anti-human IgG-APC, 1: 6,000 dilution, Jackson Immuno Research) was added. After 30 minutes at 4 ° C., cells were washed twice and resuspended in 150 μL FACS buffer. Fluorescence intensity was determined by flow cytometry (BD FACSVerse, Franklin Lakes, NJ) and expressed as median fluorescence intensity (MFI-Median) for U937 cells and ExpiCHO-S cells. Curves were fitted by nonlinear regression using a sigmoid dose-response equation with variable slope (four parameters) in GraphPad Prism (version 7.02 for Windows, GraphPad, San Diego, CA). EC 50 values were calculated as concentrations in μg / mL which provided a response between the bottom and top of the curve when using a 4-parameter logistic fit.
결과result
ELISA 어세이: 항체 1-9 및 기준 항체에 대한 ELISA로 얻어진 huSIRPα1, huSIRPαBIT, huSIRPβ1, huSIRPβ1v2, huSIRPγ, cySIRPα에의 결합을 위한 EC50 값이 표 2에 요약되어 있다. 모든 항체가 huSIRPα1 및 huSIRPαBIT에 결합한다. 항체 29AM4-5huIgG1LALA 및 12C4huIgG1LALA는 huSIRPβ1v1, huSIRPβ1v2, 및 huSIRPγ에 결합한다. 항체 2-6, 8 및 9는 huSIRPβ1v1 및 huSIRPγ에 대해 낮은 친화성을 나타낸다. 항체 7은 huSIRPβ1v1에는 결합하지만, huSIRPβ1v2 및 huSIRPγ에 대해 낮은 친화성을 갖는다. 항체 1은 huSIRPβ1v2 및 huSIRPγ에 결합한다. ELISA Assays: EC 50 values for binding to huSIRPα 1 , huSIRPα BIT , huSIRPβ 1 , huSIRPβ 1v2 , huSIRPγ, cySIRPα obtained by ELISA against Antibodies 1-9 and reference antibodies are summarized in Table 2. All antibodies were huSIRPα 1 and binds to huSIRPα BIT Antibodies 29 AM4-5huIgG 1 LALA and 12C4huIgG 1 LALA bind to huSIRPβ 1v1 , huSIRPβ 1v2 , and huSIRPγ. Antibodies 2-6, 8 and 9 are huSIRPβ 1v1 and low affinity for huSIRPγ. 7 is an antibody binding but is huSIRPβ 1v1, 1v2, and huSIRPβ has low affinity for huSIRPγ.
SPR 어세이: 기준 항체 KWAR23, huIgG112C4LALA 및 SE5A5(상업 공급자로부터 구입)와 비교하여 항체 4, 7, 10-14의 huSIRPα1, huSIRPαBIT 및 huSIRPγ에의 결합을 위한 KD 값이 표 3에 요약되어 있다. 항체 4, 7, 10-14는 huSIRPα1 및 huSIRPαBIT 둘 모두에 결합하고 huSIRPγ에 결합하지 않는다. 모든 기준 항체는 huSIRPγ에 결합한다. SPR Assays: huSIRPα 1 , huSIRPα BIT and the
유세포 분석 어세이: 세포 상에서 발현되는 huSIRPα1, huSIRPαBIT, 및/또는 cySIRPα에 대한 각종 항체의 결합이 유세포 분석에 의해 결정되었다. 결합은 EC50 값으로 표시되며, 표 4에 제시되어 있다. 항체 2, 4, 5, 7, 8, 10-14는 huSIRPα1, huSIRPαBIT 및 cySIRPα에 결합한다. 항체 2, 4, 5, 7, 8, 10-14는 낮은 ㎍/mL 범위에서 cySIRPα에 결합한다. Flow Cytometry Assay: Binding of various antibodies to huSIRPα 1 , huSIRPα BIT , and / or cySIRPα expressed on cells was determined by flow cytometry. Binding is represented by EC 50 values and is shown in Table 4.
CD47-SIRPα 결합의 항체 블로킹Antibody Blocking of CD47-SIRPα Binding
실험Experiment
SIRPα1 또는 SIRPαBIT로 형질감염된 CHO 세포 또는 대조군으로서 모체 CHO 세포를 투명한 바닥을 갖는 웰 플레이트 중의 20 ㎕ 세포 배지에 시딩하고 밤새 인큐베이트했다. 항체 1-9, 29AM4-5huIgG1LALA 또는 12C4huIgG1LALA 기준 항체를 His tag®CD47 및 항-His tag® 형광 검출 항체의 혼합물과 함께 웰에 첨가하고 2시간 동안 인큐베이트했다. 인큐베이션 후, 세포를 세포 세척 버퍼로 세척했다. 스크리닝 시스템(CellInsight®, Thermo Scientific®)을 사용하여 형광을 측정하고 세포당 총 형광을 결정하였다.SIRPα 1 or CHO cells transfected with SIRPα BIT or parental CHO cells as a control were seeded in 20 μl cell medium in well plates with a clear bottom and incubated overnight. Antibody 1-9, 29 AM4-5huIgG 1 LALA or 12C4huIgG 1 LALA reference antibody was added to the wells with a mixture of His tag®CD47 and anti-His tag® fluorescent detection antibody and incubated for 2 hours. After incubation, cells were washed with cell wash buffer. Screening systems (CellInsight®, Thermo Scientific®) were used to measure fluorescence and determine total fluorescence per cell.
결과result
항체 29AM4-5huIgG1LALA, 12C4huIgG1LALA, 3 및 7은 huSIRPα1을 발현하는 CHO 세포 및 huSIRPαBIT를 발현하는 CHO 세포 둘 다에 대한 CD47의 결합을 완벽하게 차단하고, 항체 1, 2, 4-6, 8 및 9는 huSIRPα1을 발현하는 CHO 세포 및 huSIRPαBIT를 발현하는 CHO 세포에 대한 CD47의 결합을 모두 차단하지 못한다.Antibodies 29 AM4-5huIgG 1 LALA, 12C4huIgG 1 LALA, 3 and 7 completely block binding of CD47 to both CHO cells expressing huSIRPα 1 and CHO cells expressing huSIRPα BIT , and
ADCC 어세이ADCC Assay
SIRPα1 또는 SIRPαBIT에 대해 동형 접합성인 도너의 호중구를 단리하고 문헌[Chao et al. PNAS 2011, 108(45), 18342-18347]의 방법에 따라 배양했다. ADCC는 51Cr 방출 어세이 또는 비방사성 유로퓸 TDA (EuTDA) 세포독성 어세이(DELFIA, PerkinElmer)를 이용하여 결정되었다. SKBR3 세포가 표적 세포로서 사용되었고 100 μCi 51Cr (Perkin-Elmer)로 37℃에서 90분간, 또는 비스(아세톡시메틸) 2,2':6',2"-터피리딘-6,6"-디카르복실레이트(BATDA 시약 Delfia)로 37℃에서 5분간 표지되었다. PBS로 2회 세척 후, 웰당 5x103 표적 세포를, 96-웰 U-바닥 플레이트에서, 10% (v/v) 송아지 태 혈청(FCS)이 보충된 IMDM 배양 배지에서, 호중구와 함께, 이펙터 대 표적 세포 비 50:1에서 적절한 항체의 존재 하에, 37℃ 및 5% CO2에서 4시간 동안 인큐베이트했다. 인큐베이션 후, 상청액을 수확하고 감마 카운터(Wallac)에서 방사능에 대해 분석하거나 또는 유로퓸 용액(DELFIA, PerkinElmer)에 첨가하고 유로퓸 2,2':6',2"-터피리딘-6,6"-디카르복실산(EuTDA) 형광을 스펙트로플루오로미터(Envision, PerkinElmer)를 사용하여 측정하였다. 세포독성의 백분율을 [(실험적 방출-자발적 방출) / (총 방출-자발적 방출)] x 100%로 계산하였다. 모든 조건을 2회 및/또는 3회 측정하였다.Neutrophils of donors homozygous for SIRPα 1 or SIRPα BIT were isolated and described by Chao et al. PNAS 2011, 108 (45), 18342-18347]. ADCC was determined using a 51 Cr release assay or nonradioactive Europium TDA (EuTDA) cytotoxicity assay (DELFIA, PerkinElmer). SKBR3 cells were used as target cells and 90 min at 37 ° C. with 100 μCi 51 Cr (Perkin-Elmer), or bis (acetoxymethyl) 2,2 ': 6', 2 "-terpyridine-6,6"- Labeled with dicarboxylate (BATDA reagent Delfia) at 37 ° C. for 5 minutes. After washing twice with PBS, 5 × 10 3 target cells per well, in 96-well U-bottom plates, in neutrophils, with neutrophils, in IMDM culture medium supplemented with 10% (v / v) calf serum (FCS) Incubated at 37 ° C. and 5% CO 2 for 4 hours in the presence of appropriate antibody at a target cell ratio of 50: 1. After incubation, the supernatant is harvested and analyzed for radioactivity on a gamma counter (Wallac) or added to europium solution (DELFIA, PerkinElmer) and europium 2,2 ': 6', 2 "-terpyridine-6,6" -dica Leric acid (EuTDA) fluorescence was measured using a spectrofluorometer (Envision, PerkinElmer). The percentage of cytotoxicity was calculated as [(experimental release-voluntary release) / (total release-voluntary release)] × 100%. All conditions were measured twice and / or three times.
ADCC 데이터 12C4huIgGADCC Data 12C4huIgG 1One LALA vs 12C4IgGLALA vs 12C4IgG 1One
도 1은 ADCC 어세이의 결과를 %세포독성으로서 도시하고 있다. 이펙터 세포로서 호중구 및 트라스투주맙 단독을 사용하여 SKBR3 세포에서 측정된 %세포독성은 뮤린 12C4 항체(mu12C4)와 조합된 트라스투주맙의 %세포독성보다 작다. 12C4 가변 영역이 인간 IgG1 불변 영역에 이식된 항체(12C4huIgG1)와 조합된 트라스투주맙은 저 농도의 12C4huIgG1에서 트라스투주맙 단독과 비교하여 유사한 %세포독성을 나타낸다. 보다 높은 농도의 12C4huIgG1에서는, %세포독성의 감소가 관찰된다. 아미노산 치환 L234A 및 L235A를 포함하는 인간 IgG1 불변 영역에 12C4 가변 영역이 이식된 항체(12C4huIgG1LALA)와 조합된 트라스투주맙은 트라스투주맙 단독의 %세포독성과 비교하여 증가된 %세포독성을 나타내고, 12C4huIgG1 및 트라스투주맙의 조합과 비교하여 증가된 %세포독성을 나타낸다.1 depicts the results of ADCC assay as% cytotoxicity. The% cytotoxicity measured in SKBR3 cells using neutrophils and trastuzumab alone as effector cells is less than the% cytotoxicity of trastuzumab in combination with murine 12C4 antibody (mu12C4). Trastuzumab in combination with an antibody (12C4huIgG 1 ) in which a 12C4 variable region was implanted in a human IgG 1 constant region shows similar% cytotoxicity compared to trastuzumab alone at low concentrations of 12C4huIgG 1 . At higher concentrations of 12C4huIgG 1 , a decrease in% cytotoxicity is observed. Trastuzumab in combination with an antibody implanted with a 12C4 variable region in a human IgG 1 constant region comprising amino acid substitutions L234A and L235A (12C4huIgG 1 LALA) provides increased% cytotoxicity compared to% cytotoxicity of trastuzumab alone. And increased% cytotoxicity compared to the combination of 12C4huIgG 1 and trastuzumab.
ADCC 데이터ADCC data
도 2는 12C4huIgG1LALA와 비교하여, 트라스투주맙과 조합된 아미노산 치환 L234A 및 L235A(LALA)을 포함하는 인간 IgG1 불변 영역을 갖는 항체 1-9의 존재하의 트라스투주맙(100%로 설정)에 상대적인 인간 호중구에 의한 %ADCC를 비교하고 있다. 뮤린 항-CD47 항체의 VR 및 아미노산 치환 L234A 및 L235A를 포함하는 인간 IgG1 불변 영역을 갖는 B6H12IgG1LALA, 및 비히클(트라스투주맙 무함유)을 각각 양성 및 음성 대조군으로서 사용했다. 채워진 사각형(■)은 SIRPαBIT 변이(SIRPαBIT에 대해 동형 접합성임)를 갖는 도너의 호중구를 사용하여 측정된 값이고, 빈 원형(○)은 SIRPα1 변이(SIRPα1에 대해 동형 접합성임)를 갖는 도너의 호중구를 사용하여 측정된 값이다. 모든 항체의 경우 평균 ADCC가 트라스투주맙 단독에 비해 증가했다. 항체 1, 2, 4, 5, 7 및 8의 경우 평균 ADCC 증가가 12C4huIgG1LALA-유도 ADCC 증가보다 훨씬 더 향상되었다. 항체당 도너당 ADCC 증가를 비교했을 때, 항체 1, 3-6, 8 및 9는 12C4huIgG1LALA보다 ADCC의 증가율의 변동이 더 적게 나타난다.2 shows trastuzumab (set at 100%) in the presence of antibody 1-9 with human IgG 1 constant region comprising amino acid substitutions L234A and L235A (LALA) in combination with trastuzumab compared to 12C4huIgG 1 LALA % ADCC by human neutrophils is compared. B6H12IgG 1 LALA with human IgG 1 constant region comprising the VR and amino acid substitutions L234A and L235A of the murine anti-CD47 antibody and vehicle (without trastuzumab) were used as positive and negative controls, respectively. Filled squares (■) are measured using neutrophils in donors with SIRPα BIT variation (homozygous for SIRPα BIT ), and empty circles (○) show SIRPα 1 variation (homozygous for SIRPα 1 ). It is the value measured using the neutrophil of the donor which has. For all antibodies, the average ADCC was increased compared to trastuzumab alone. For
도 3은, 트라스투주맙 단독, 및 각종 농도의 12C4huIgG1LALA와 조합된 트라스투주맙과 비교하여, 트라스투주맙과 조합된 아미노산 치환 L234A 및 L235A(LALA)를 포함하는 인간 IgG1 불변 영역을 갖는 각종 농도의 키메라 항체 4 및 7 및 인간화 항체 10 및 14의 존재하에 인간 호중구에 의한 %ADCC를 비교하고 있다. SIRPαBIT에 대해 동형 접합성인 2 도너의 호중구가 사용되었다. 심지어 낮은 농도에서 항체 4, 7, 10 및 14는 ADCC를 증가시킨다. ADCC 증가는 농도 의존적이다.FIG. 3 shows human IgG 1 constant regions comprising amino acid substitutions L234A and L235A (LALA) in combination with trastuzumab compared to trastuzumab alone and in combination with 12C4huIgG 1 LALA at various concentrations. % ADCC by human neutrophils is compared in the presence of various concentrations of
도 4는, 트라스투주맙(Tmab) 단독 및 12C4huIgG1LALA의 %ADCC와 비교하여, 트라스투주맙과 조합된 항체 4, 7, 10, 13, 14, 15 및 16의 존재하에서 인간 호중구에 의한 %ADCC를 비교하고 있다. 모든 항체가 트라스투주맙 단독과 비교하여 ADCC를 증가시킨다. 트라스투주맙과 조합된 항체 4, 7, 10, 13, 14, 15 및 16의 존재하에서 대부분의 도너의 호중구에 의한 ADCC 증가는 트라스투주맙과 조합된 12C4huIgG1LALA와 비교하여 유사하거나 증가된다.4% by human neutrophils in the presence of
(카밧의 방법에 의해 결정된) 중쇄(HC) 및 경쇄(LC) 가변 영역(VR) 아미노산 서열에서 밑줄친 CDR1, CDR2 및 CDR3 아미노산 서열을 갖는 서열 목록Sequence listing with CDR1, CDR2, and CDR3 amino acid sequences underlined in heavy (HC) and light (LC) variable region (VR) amino acid sequences (as determined by Kabat's method)
SEQUENCE LISTING <110> Synthon Biopharmaceuticals B.V. VERHEIJDEN Gijsbertus Franciscus Maria ROUWENDAL Gerard Johan Adolph ARENDS Roland Jan BERG, VAN DEN Timo Kars MATLUNG Hanke Lottie SZILAGYI Katarina <120> Anti SIRPalpha antibodies with a LALA mutation <130> P1703PC00/PB-078 <140> PCT/EP2018/062473 <141> 2018-05-15 <160> 40 <170> BiSSAP 1.3.6 <210> 1 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:1 (HC VR 1) <400> 1 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Ala 20 25 30 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Pro 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Leu 85 90 95 Trp Ala Ala Ser Asn Tyr Tyr Met Ala Leu Trp Gly Pro Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 2 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:2 (LC VR 1) <400> 2 Ala Ile Lys Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Ser Ile Asn Cys Gln Ala Ser Glu Asp Ile Glu Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Asp Tyr Tyr Ser Ser Ser 85 90 95 Gly Asp Thr Gly Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 3 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:3 (HC VR 2) <400> 3 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Ala 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Thr Gly Gly Ala Thr Ser Tyr Ala Thr Trp Ala Lys Gly 50 55 60 Gln Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Asp 85 90 95 Arg Asp Gly Tyr Ala Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 4 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:4 (LC VR 2) <400> 4 Gln Ile Val Met Thr Gln Thr Pro Phe Ser Val Ser Ala Val Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser His Asn Ile Gly Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Ile Ser Tyr 85 90 95 Val His Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 5 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:5 (HC VR 3) <400> 5 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Ala Cys Thr Val Ser Gly Phe Ser Leu Ile Ser Tyr Tyr 20 25 30 Ile Ser Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Ile Ile Asn Ile Gly Gly Gly Ala Ser Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Pro Glu Asp Thr Ala Thr Tyr Phe Cys Ala Met Ser Tyr 85 90 95 Gly Met Asp Thr Gly Ala Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 6 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:6 (LC VR 3) <400> 6 Ala Gln Val Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Ser Cys Gln Ser Ser Glu Ser Val Tyr Lys Asn 20 25 30 Asn Phe Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60 Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu 65 70 75 80 Glu Ser Asp Asp Ala Ala Thr Tyr Phe Cys Gln Gly Gly Tyr Arg Thr 85 90 95 Asp Ile Tyr Pro Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 7 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:7 (HC VR 4) <400> 7 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Gly Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val 20 25 30 Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Asn 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly 85 90 95 Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 8 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:8 (LC VR 4) <400> 8 Asp Ile Val Met Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Gly Gln Ser Ile Asn Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asp Leu Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg 85 90 95 Ser Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 <210> 9 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:9 (HC VR 5) <400> 9 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val 20 25 30 Met Gly Trp Phe Arg Gln Ala Ala Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Tyr Ile Asn Ala Asp Gly Ser Pro Tyr Tyr Ala Thr Trp Val Asn Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Pro Thr Thr Met Asp Leu Lys Ile Asn 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly 85 90 95 Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 10 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:10 (LC VR 5) <400> 10 Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Asn Arg Tyr 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Glu Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asp Leu Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Tyr Ile Ser Arg 85 90 95 Thr Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 <210> 11 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:11 (HC VR 6) <400> 11 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Thr 20 25 30 Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Ser 85 90 95 Ser Asp Gly Tyr Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 12 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:12 (LC VR 6) <400> 12 Gly Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Gly Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Arg Gly Ser Gly Thr His Phe Thr Leu Thr Ile Ser Asp Val Gln Ser 65 70 75 80 Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Thr Val Thr Ala Ala Ser 85 90 95 Asn Val Asp Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 13 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:13 (HC VR 7) <400> 13 Arg Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser His Gly 20 25 30 Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Thr Ile Gly Thr Gly Val Ile Thr Tyr Phe Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Gly Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Ser 85 90 95 Ala Trp Asn Asp Pro Phe Asp Pro Trp Gly Pro Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 14 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:14 (LC VR 7) <400> 14 Ala Leu Val Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Thr Lys Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn 20 25 30 Asn Asp Leu Ala Trp Tyr Gln His Lys Pro Gly Gln Pro Pro Lys Leu 35 40 45 Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Thr Gly Val 65 70 75 80 Gln Ser Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp 85 90 95 Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 15 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:15 (HC VR 8) <400> 15 Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Ala Ser Gly Val Asp Leu Ser Asn Tyr Ala 20 25 30 Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Ala Gly Gly Ser Thr Ser Tyr Ala Thr Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg His Arg 85 90 95 Ser Asp Gly Tyr Asp Tyr Phe His Leu Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 16 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:16 (LC VR 8) <400> 16 Ala Ile Asp Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Gln Ser 65 70 75 80 Asp Asp Ala Ala Ala Tyr Tyr Cys Gln Gln Gly Tyr Ala Val Ser Tyr 85 90 95 Val Glu Asn Ile Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 17 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:17 (HC VR 9) <400> 17 Gln Ser Met Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asn Tyr Gly 20 25 30 Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Gly Gly Ser Asp Ile Thr Ala Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Thr Ile 65 70 75 80 Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Lys Ser 85 90 95 Tyr Thr Asn Gly Met Asp Tyr Tyr Asn Ile Trp Gly Pro Gly Thr Leu 100 105 110 Val Thr Val Ser Leu 115 <210> 18 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:18 (LC VR 9) <400> 18 Ala Phe Asp Leu Thr Gln Thr Pro Ser Ser Val Glu Ala Pro Val Gly 1 5 10 15 Gly Thr Val Ile Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Glu Thr Gln Phe Pro Leu Thr Ile Ser Asp Leu Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Ser Arg Ser 85 90 95 Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 <210> 19 <211> 129 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:19 (HC VR 29AM4-5)) <400> 19 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Ser Tyr Tyr 20 25 30 Phe Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Val Tyr Ser Ser Phe Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Phe Thr Phe Pro Gly Leu Phe Asp Gly Phe Phe Gly Ala Tyr 100 105 110 Leu Gly Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 115 120 125 Ser <210> 20 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:20 (LC VR 29AM4-5) <400> 20 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Val Asn Trp Val Gly 85 90 95 Ala Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 21 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:21 (HC VR 12C4) <400> 21 Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Met Gln Pro Gly Gly 1 5 10 15 Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val 35 40 45 Ala Glu Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser 65 70 75 80 Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr 85 90 95 Tyr Cys Ile Arg Asp Tyr Asp Tyr Asp Ala Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 22 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:22 (LC VR 12C4) <400> 22 Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 20 25 30 Gly Tyr Asn Tyr Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln His Ser Gly 85 90 95 Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 23 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:23 (HC KWAR23 ) <400> 23 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr 20 25 30 Tyr Ile His Trp Val Gln Gln Arg Thr Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Lys Phe 50 55 60 Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr 65 70 75 80 Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser <210> 24 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:24 (LC VR KWAR23) <400> 24 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Leu Thr Cys Ser Ala Ser Ser Ser Val Ser Ser Ser 20 25 30 Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp 35 40 45 Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu 65 70 75 80 Ala Glu Asp Ala Ala Ser Tyr Phe Cys His Gln Trp Ser Ser Tyr Pro 85 90 95 Arg Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 25 <211> 330 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO 25: (human IgG1 antibody HC constant region) <400> 25 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 26 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO 26: (human IgG antibody LC ? constant region) <400> 26 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 27 <211> 330 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO 27: (human IgG1 antibody HC constant region LALA mutant (mutations underlined) <400> 27 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 28 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:28 (leader sequence antibodies 1-9) <400> 28 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val His Ser <210> 29 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:29 (HAVT20 leader sequence) <400> 29 Met Ala Cys Pro Gly Phe Leu Trp Ala Leu Val Ile Ser Thr Cys Leu 1 5 10 15 Glu Phe Ser Met Ala 20 <210> 30 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:30 (HC10 <400> 30 Lys Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu 1 5 10 15 Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr Val Met 20 25 30 Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ile 35 40 45 Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly Arg 50 55 60 Phe Thr Ile Ser Lys Asp Asn Ser Glu Gly Met Val Tyr Leu Gln Met 65 70 75 80 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val 85 90 95 Gly Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 <210> 31 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:31 (LC 10) <400> 31 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Gln Ala Gly Gln Ser Ile Asn Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg 85 90 95 Ser Tyr Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 32 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:32 (HC VR 11) <400> 32 Glu Val Lys Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Val Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn 50 55 60 Gly Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Gln Met 65 70 75 80 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val 85 90 95 Gly Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 <210> 33 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:33 (LC VR 11) <400> 33 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Gly Gln Ser Ile Asn Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg 85 90 95 Ser Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 34 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:34 (HC VR 12) <400> 34 Val Gln Leu Val Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Ser Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val 20 25 30 Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Asn 65 70 75 80 Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly 85 90 95 Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 35 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:34 (HC VR 12) <400> 35 Val Gln Leu Val Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Ser Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val 20 25 30 Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Asn 65 70 75 80 Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly 85 90 95 Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 36 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:36 (LC VR 13) <400> 36 Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn 20 25 30 Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp 85 90 95 Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 37 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:37 (LC VR 14 +16) <400> 37 Asp Ile Glu Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Leu Thr Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn 20 25 30 Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp 85 90 95 Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 38 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:38 (LC VR 15) <400> 38 Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn 20 25 30 Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp 85 90 95 Glu Ala Asp Asn Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 39 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:39 (leader sequence heavy chains 10-14) <400> 39 Met Gly Trp Thr Leu Val Phe Leu Phe Leu Leu Ser Val Thr Ala Gly 1 5 10 15 Val His Ser <210> 40 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> SEQ ID NO:40 (leader sequence light chains 10, 11, 13-16) <400> 40 Met Val Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln 1 5 10 15 Gly Thr Arg Cys 20 SEQUENCE LISTING <110> Synthon Biopharmaceuticals B.V. VERHEIJDEN Gijsbertus Franciscus Maria ROUWENDAL Gerard Johan Adolph ARENDS Roland Jan BERG, VAN DEN Timo Kars MATLUNG Hanke Lottie SZILAGYI Katarina <120> Anti SIRPalpha antibodies with a LALA mutation <130> P1703PC00 / PB-078 <140> PCT / EP2018 / 062473 <141> 2018-05-15 <160> 40 <170> BiSSAP 1.3.6 <210> 1 <211> 117 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 1 (HC VR 1) <400> 1 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Ala 20 25 30 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Ser Ser Gly Gly Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Pro 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Leu 85 90 95 Trp Ala Ala Ser Asn Tyr Tyr Met Ala Leu Trp Gly Pro Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 2 <211> 111 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 2 (LC VR 1) <400> 2 Ala Ile Lys Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Ser Ile Asn Cys Gln Ala Ser Glu Asp Ile Glu Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Asp Tyr Tyr Ser Ser Ser 85 90 95 Gly Asp Thr Gly Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 3 <211> 116 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 3 (HC VR 2) <400> 3 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Ala 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Thr Gly Gly Ala Thr Ser Tyr Ala Thr Trp Ala Lys Gly 50 55 60 Gln Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Asp 85 90 95 Arg Asp Gly Tyr Ala Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 4 <211> 110 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 4 (LC VR 2) <400> 4 Gln Ile Val Met Thr Gln Thr Pro Phe Ser Val Ser Ala Val Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser His Asn Ile Gly Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Ile Ser Tyr 85 90 95 Val His Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 5 <211> 116 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 5 (HC VR 3) <400> 5 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Ala Cys Thr Val Ser Gly Phe Ser Leu Ile Ser Tyr Tyr 20 25 30 Ile Ser Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Ile Ile Asn Ile Gly Gly Gly Ala Ser Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Pro Glu Asp Thr Ala Thr Tyr Phe Cys Ala Met Ser Tyr 85 90 95 Gly Met Asp Thr Gly Ala Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 6 <211> 110 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 6 (LC VR 3) <400> 6 Ala Gln Val Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Ser Cys Gln Ser Ser Glu Ser Val Tyr Lys Asn 20 25 30 Asn Phe Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60 Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu 65 70 75 80 Glu Ser Asp Asp Ala Ala Thr Tyr Phe Cys Gln Gly Gly Tyr Arg Thr 85 90 95 Asp Ile Tyr Pro Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 7 <211> 116 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 7 (HC VR 4) <400> 7 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Gly Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val 20 25 30 Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Asn 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly 85 90 95 Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 8 <211> 109 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 8 (LC VR 4) <400> 8 Asp Ile Val Met Thr Gln Thr Pro Ser Ser Val Glu Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Gly Gln Ser Ile Asn Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asp Leu Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg 85 90 95 Ser Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 <210> 9 <211> 116 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 9 (HC VR 5) <400> 9 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val 20 25 30 Met Gly Trp Phe Arg Gln Ala Ala Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Tyr Ile Asn Ala Asp Gly Ser Pro Tyr Tyr Ala Thr Trp Val Asn Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Pro Thr Thr Met Asp Leu Lys Ile Asn 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly 85 90 95 Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 10 <211> 109 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 10 (LC VR 5) <400> 10 Asp Ile Val Met Thr Gln Thr Pro Ala Ser Val Glu Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Asn Arg Tyr 20 25 30 Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Glu Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asp Leu Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Tyr Ile Ser Arg 85 90 95 Thr Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 <210> 11 <211> 116 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 11 (HC VR 6) <400> 11 Gln Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr Thr 20 25 30 Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Ala Gly Gly Ser Thr Ala Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Ser 85 90 95 Ser Asp Gly Tyr Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 12 <211> 111 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 12 (LC VR 6) <400> 12 Gly Val Val Met Thr Gln Thr Pro Ser Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Ile Gly Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Arg Gly Ser Gly Thr His Phe Thr Leu Thr Ile Ser Asp Val Gln Ser 65 70 75 80 Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Thr Val Thr Ala Ala Ser 85 90 95 Asn Val Asp Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 13 <211> 115 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 13 (HC VR 7) <400> 13 Arg Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser His Gly 20 25 30 Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Thr Ile Gly Thr Gly Val Ile Thr Tyr Phe Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Gly Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Ile Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Ser 85 90 95 Ala Trp Asn Asp Pro Phe Asp Pro Trp Gly Pro Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 14 <211> 111 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 14 (LC VR 7) <400> 14 Ala Leu Val Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr Thr Lys Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn 20 25 30 Asn Asp Leu Ala Trp Tyr Gln His Lys Pro Gly Gln Pro Pro Lys Leu 35 40 45 Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Thr Gly Val 65 70 75 80 Gln Ser Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp 85 90 95 Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 15 <211> 116 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 15 (HC VR 8) <400> 15 Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Ala Ser Gly Val Asp Leu Ser Asn Tyr Ala 20 25 30 Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Ala Gly Gly Ser Thr Ser Tyr Ala Thr Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg His Arg 85 90 95 Ser Asp Gly Tyr Asp Tyr Phe His Leu Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Leu 115 <210> 16 <211> 110 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 16 (LC VR 8) <400> 16 Ala Ile Asp Met Thr Gln Thr Pro Ala Ser Val Ser Glu Pro Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Gln Ser 65 70 75 80 Asp Asp Ala Ala Ala Tyr Tyr Cys Gln Gln Gly Tyr Ala Val Ser Tyr 85 90 95 Val Glu Asn Ile Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <210> 17 <211> 117 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 17 (HC VR 9) <400> 17 Gln Ser Met Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asn Tyr Gly 20 25 30 Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Gly Gly Ser Asp Ile Thr Ala Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Thr Ile 65 70 75 80 Thr Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Lys Ser 85 90 95 Tyr Thr Asn Gly Met Asp Tyr Tyr Asn Ile Trp Gly Pro Gly Thr Leu 100 105 110 Val Thr Val Ser Leu 115 <210> 18 <211> 108 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 18 (LC VR 9) <400> 18 Ala Phe Asp Leu Thr Gln Thr Pro Ser Ser Val Glu Ala Pro Val Gly 1 5 10 15 Gly Thr Val Ile Ile Lys Cys Gln Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Glu Thr Gln Phe Pro Leu Thr Ile Ser Asp Leu Glu Ser 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Tyr Tyr Gly Ser Arg Ser 85 90 95 Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 <210> 19 <211> 129 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 19 (HC VR 29 AM4-5) <400> 19 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Ser Tyr Tyr 20 25 30 Phe Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Val Tyr Ser Ser Phe Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Phe Thr Phe Pro Gly Leu Phe Asp Gly Phe Phe Gly Ala Tyr 100 105 110 Leu Gly Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 115 120 125 Ser <210> 20 <211> 110 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 20 (LC VR 29 AM4-5) <400> 20 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Val Asn Trp Val Gly 85 90 95 Ala Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 21 <211> 121 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 21 (HC VR 12C4) <400> 21 Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Met Gln Pro Gly Gly 1 5 10 15 Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val 35 40 45 Ala Glu Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser 65 70 75 80 Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr 85 90 95 Tyr Cys Ile Arg Asp Tyr Asp Tyr Asp Ala Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 22 <211> 111 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 22 (LC VR 12C4) <400> 22 Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 20 25 30 Gly Tyr Asn Tyr Met Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln His Ser Gly 85 90 95 Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 23 <211> 113 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 23 (HC KWAR23) <400> 23 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr 20 25 30 Tyr Ile His Trp Val Gln Gln Arg Thr Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asp Pro Glu Asp Gly Glu Thr Lys Tyr Ala Pro Lys Phe 50 55 60 Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr 65 70 75 80 Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110 Ser <210> 24 <211> 108 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 24 (LC VR KWAR23) <400> 24 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Leu Thr Cys Ser Ala Ser Ser Ser Val Ser Ser Ser 20 25 30 Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp 35 40 45 Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu 65 70 75 80 Ala Glu Asp Ala Ala Ser Tyr Phe Cys His Gln Trp Ser Ser Tyr Pro 85 90 95 Arg Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 25 <211> 330 <212> PRT <213> Artificial Sequence <220> SEQ ID NO 25: (human IgG1 antibody HC constant region) <400> 25 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 26 <211> 107 <212> PRT <213> Artificial Sequence <220> SEQ ID NO 26: (human IgG antibody LC-constant region) <400> 26 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 27 <211> 330 <212> PRT <213> Artificial Sequence <220> SEQ ID NO 27: (human IgG1 antibody HC constant region LALA mutant (mutations underlined) <400> 27 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 28 <211> 19 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 28 (leader sequence antibodies 1-9) <400> 28 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val his ser <210> 29 <211> 21 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 29 (HAVT20 leader sequence) <400> 29 Met Ala Cys Pro Gly Phe Leu Trp Ala Leu Val Ile Ser Thr Cys Leu 1 5 10 15 Glu Phe Ser Met Ala 20 <210> 30 <211> 117 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 30 (HC10) <400> 30 Lys Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu 1 5 10 15 Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr Val Met 20 25 30 Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ile 35 40 45 Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly Arg 50 55 60 Phe Thr Ile Ser Lys Asp Asn Ser Glu Gly Met Val Tyr Leu Gln Met 65 70 75 80 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val 85 90 95 Gly Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 <210> 31 <211> 109 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 31 (LC 10) <400> 31 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Gln Ala Gly Gln Ser Ile Asn Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg 85 90 95 Ser Tyr Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 32 <211> 117 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 32 (HC VR 11) <400> 32 Glu Val Lys Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Val Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn 50 55 60 Gly Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Gln Met 65 70 75 80 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val 85 90 95 Gly Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 <210> 33 <211> 109 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 33 (LC VR 11) <400> 33 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Gly Gln Ser Ile Asn Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Ser Trp His Tyr Ile Ser Arg 85 90 95 Ser Tyr Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 34 <211> 116 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 34 (HC VR 12) <400> 34 Val Gln Leu Val Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Ser Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val 20 25 30 Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Asn 65 70 75 80 Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly 85 90 95 Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 35 <211> 116 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 34 (HC VR 12) <400> 35 Val Gln Leu Val Glu Ser Gly Gly Arg Leu Val Gln Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Ser Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Val 20 25 30 Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45 Ile Ile Ser Ser Ser Gly Ser Pro Tyr Tyr Ala Ser Trp Val Asn Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Met Asp Leu Lys Met Asn 65 70 75 80 Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Val Gly 85 90 95 Pro Leu Gly Val Asp Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 36 <211> 111 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 36 (LC VR 13) <400> 36 Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn 20 25 30 Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp 85 90 95 Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 37 <211> 111 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 37 (LC VR 14 +16) <400> 37 Asp Ile Glu Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Leu Thr Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn 20 25 30 Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp 85 90 95 Glu Ala Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 38 <211> 111 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 38 (LC VR 15) <400> 38 Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Val Tyr Gly Asn 20 25 30 Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Glu Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Leu Ala Ser Thr Leu Ala Thr Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Gly Gly Asp Asp 85 90 95 Glu Ala Asp Asn Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 39 <211> 19 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 39 (leader sequence heavy chains 10-14) <400> 39 Met Gly Trp Thr Leu Val Phe Leu Phe Leu Leu Ser Val Thr Ala Gly 1 5 10 15 Val his ser <210> 40 <211> 20 <212> PRT <213> Artificial Sequence <220> SEQ ID NO: 40 (leader sequence light chains 10, 11, 13-16) <400> 40 Met Val Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln 1 5 10 15 Gly Thr Arg Cys 20
Claims (15)
a. 서열 번호 3의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 4의 CDR1, CDR2 및 CDR3 아미노산 서열;
b. 서열 번호 5의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 6의 CDR1, CDR2 및 CDR3 아미노산 서열;
c. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열;
d. 서열 번호 9의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 10의 CDR1, CDR2 및 CDR3 아미노산 서열;
e. 서열 번호 11의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 12의 CDR1, CDR2 및 CDR3 아미노산 서열;
f. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열;
g. 서열 번호 15의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 16의 CDR1, CDR2 및 CDR3 아미노산 서열; 및
h. 서열 번호 17의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 18의 CDR1, CDR2 및 CDR3 아미노산 서열;
여기서 CDR은 카밧(Kabat) 넘버링에 따라 결정된다.An anti-SIRPα antibody or antigen binding fragment thereof comprising a heavy chain (HC) and a light chain (LC) variable region (VR) complementarity determining region (CDR) selected from the group consisting of a to h:
a. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 3 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 4;
b. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 5 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 6;
c. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8;
d. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 9 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 10;
e. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 11 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 12;
f. The CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13 and the CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14;
g. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 15 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 16; And
h. The CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 17 and the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 18;
CDRs are determined according to Kabat numbering.
a. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열; 및
b. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열
로 이루어진 군에서 선택되는 HCVR 및 LCVR CDR을 포함하고, 인간화 항체인 항체.The method of claim 2,
a. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7 and CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8; And
b. CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 13 and CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 14
An antibody comprising a HCVR and LCVR CDR selected from the group consisting of and being a humanized antibody.
a. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 30의 HCVR 아미노산 서열 및 서열 번호 31의 LCVR 아미노산 서열;
b. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 32의 HCVR 아미노산 서열 및 서열 번호 33의 LCVR 아미노산 서열;
c. 서열 번호 7의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 8의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 34의 HCVR 아미노산 서열 및 서열 번호 8의 LCVR 아미노산 서열;
d. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 36의 LCVR 아미노산 서열;
e. 서열 번호 13의 CDR1, CDR2 및 CDR3 아미노산 서열, 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 35의 HCVR 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열;
f. 서열 번호 13의 HCVR 아미노산 서열, 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 38의 LCVR 아미노산 서열; 또는
g. 서열 번호 13의 HCVR 아미노산 서열, 서열 번호 14의 CDR1, CDR2 및 CDR3 아미노산 서열 및 서열 번호 37의 LCVR 아미노산 서열
을 포함하는 인간화 항체.The method of claim 3,
a. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8, HCVR amino acid sequences of SEQ ID NO: 30, and LCVR amino acid sequences of SEQ ID NO: 31;
b. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8, HCVR amino acid sequences of SEQ ID NO: 32, and LCVR amino acid sequences of SEQ ID NO: 33;
c. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 7, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 8, HCVR amino acid sequences of SEQ ID NO: 34 and LCVR amino acid sequences of SEQ ID NO: 8;
d. CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13, CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14, HCVR amino acid sequences of SEQ ID NO: 35 and LCVR amino acid sequences of SEQ ID NO: 36;
e. The CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 13, the CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14 and the HCVR amino acid sequences of SEQ ID NO: 35 and the LCVR amino acid sequences of SEQ ID NO: 37;
f. The HCVR amino acid sequence of SEQ ID NO: 13, the CDR1, CDR2 and CDR3 amino acid sequences of SEQ ID NO: 14 and the LCVR amino acid sequence of SEQ ID NO: 38; or
g. HCVR amino acid sequence of SEQ ID NO: 13, CDR1, CDR2 and CDR3 amino acid sequence of SEQ ID NO: 14 and LCVR amino acid sequence of SEQ ID NO: 37
Humanized antibody comprising a.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP17171285 | 2017-05-16 | ||
EP17171285.4 | 2017-05-16 | ||
PCT/EP2018/062473 WO2018210793A2 (en) | 2017-05-16 | 2018-05-15 | ANTI-SIRPα ANTIBODIES |
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KR20200005659A true KR20200005659A (en) | 2020-01-15 |
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KR1020197037055A KR20200005659A (en) | 2017-05-16 | 2018-05-15 | Anti-SIRPα antibodies |
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US (2) | US11274159B2 (en) |
EP (1) | EP3625259B1 (en) |
JP (1) | JP7171617B2 (en) |
KR (1) | KR20200005659A (en) |
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WO2018210795A1 (en) | 2018-11-22 |
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WO2018210793A3 (en) | 2018-12-20 |
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RU2019141289A3 (en) | 2021-09-17 |
US11274159B2 (en) | 2022-03-15 |
JP2020520370A (en) | 2020-07-09 |
US20210070874A1 (en) | 2021-03-11 |
CL2019003266A1 (en) | 2020-03-13 |
AU2018268304A1 (en) | 2019-11-14 |
RU2771174C2 (en) | 2022-04-28 |
EP3625259B1 (en) | 2024-04-17 |
EP3625259A2 (en) | 2020-03-25 |
RU2019141289A (en) | 2021-06-16 |
CA3063622A1 (en) | 2018-11-22 |
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